Drug dispenser

ABSTRACT

One aspect provides a drug dispenser device comprising a housing; extending from the housing, an outlet for insertion into a body cavity of a patient; provided to the housing and moveable with respect thereto, a drug discharge device having a longitudinal axis and comprising a container for storing a drug formulation to be dispensed, a discharge mechanism and a discharge channel from the container for discharge of the drug formulation to the outlet; connecting to the container, a container collar connected to the discharge device; connecting to the container collar and moveable with respect thereto along the longitudinal axis of the drug discharge device; connecting to the container collar and moveable with respect thereto along the longitudinal axis of the drug discharge device, a transfer element including an actuating portion; provided to the housing, at least one finger operable member moveable to apply an actuating force to the actuating portion of the transfer clement to move the transfer element from an initial position along the longitudinal axis in a first direction; provided to the container collar, a pre-load mechanism to prevent transfer of the actuating force to the container collar to move the drug discharge device along the longitudinal axis in the first direction to actuate the discharge mechanism until a pre-determined threshold force is overcome; and connecting the container collar with the transfer element, a biasing return mechanism acting to bias the transfer element along the longitudinal axis in a second direction to return the transfer element to its initial position.

The present patent application claims priority from U.S. ProvisionalApplication No. 60/956,950 filed on 21 Aug. 2007, which is incorporatedherein by reference in entirety.

The disclosures of U.S. Provisional Applications Nos. 60/823,134,60/823,139, 60/823,141, 60/823,143, 60/823,146, 60/823,151 and60/823,154, all filed on 22 Aug. 2006; U.S. Provisional Application No.60/894,537 filed on 13 Mar. 2007; U.S. Provisional Application No.60/956,947 filed 21 Aug. 2007, U.S. Provisional Application No.61/029,458 filed on 18 Feb. 2008 and U.S. Provisional Application No.61/035,872 filed 12 Mar. 2008, all commonly owned, are incorporatedherein by reference in their entirety.

The disclosures of the International (PCT) Patent ApplicationsWO-A-2008/023018, WO-A-2008/023019, WO-A-2008/023017, WO-A-2008/023015,WO-A-2008/023014, WO-A-2008/023013, and WO-A-2008/024728 which designatethe United States of America and claim priority from the aforementionedU.S. Provisional Application Nos. 60/823,134, 60/823,139, 60/823,141,60/823,143, 60/823,146, 60/823,151 and 60/823,154 are also incorporatedherein by reference in their entirety.

The disclosure of International (PCT) Patent ApplicationPCT/EP2008/052967 which designates the United States of America andclaims priority from the aforementioned U.S. Provisional ApplicationNos. 60/894,537 and 60/956,947 is also incorporated herein by referencein its entirety.

The present invention relates to a drug dispenser and in particular to adrug dispenser for delivering metered doses of aerosol or fluid drugformulation and adapted for use as an oral or nasal inhaler.

It is known to provide a drug dispenser, in which a drug dose isdispensed via a mouthpiece or nozzle upon the application of a force bya user to an actuating lever or similar actuating members. Typically,displacement of the actuating lever is arranged to transfer actuatingforce to a dispensing mechanism (e.g. a valve or pump) provided to adrug container, which results in dispensing of a drug dose. Suchdispensers may be arranged to dispense a single dose or mayalternatively be arranged with a reservoir containing several doses tobe dispensed.

If the actuating lever is moved in a slow, insufficiently strong,unpredictable or otherwise inadequate manner the drug may not be causedto effectively dispensed.

A drug dispenser of embodiments provided herein includes a ‘commitment’feature, which allows transfer of actuating force from the actuatorlever to the dispensing mechanism, and optionally to any includedactuation counter, only when a pre-determined threshold force has beenexceeded. This provides assurance of effective dispensing of drug and,where a counter is present, reliable counting of that dispensing, whichis only permitted to occur in response to sufficient actuating forcehaving been provided by the patient to the actuating lever to overcomethe pre-determined threshold.

The present invention in aspects thereof proposes to provide a drugdispenser that provides more efficient dispensing of drug, and inparticular, one that prevents ineffective dispensing of drug as a resultof inadequate patient actuation.

According to a first aspect of the invention there is provided a drugdispenser device according to claim 1 hereof.

The housing may have any suitable form but is in embodiments sized andshaped for ready accommodation by the hand of a patient. In particular,the housing is sized and shaped to enable one-handed operation of thedispenser device.

Extending from the housing, there is provided an outlet for insertioninto a body cavity of a patient. Where the patient body cavity is themouth of a patient, the outlet is generally shaped to define amouthpiece. Where the patient body cavity is the nose of a patient, theoutlet is generally shaped in nozzle form for receipt by a nostril ofthe patient. The outlet may be provided with a removeable protectivecover such as a mouthpiece cover or nozzle cover.

Provided to the housing and moveable with respect thereto, there is adrug discharge device. The drug discharge device has a longitudinal axisand comprises a container for storing a drug formulation to bedispensed. In embodiments, the container adopts a generally cylindricalform and the longitudinal axis is defined by the central axis of thecylinder. The container is in embodiments arranged to have a neck at oneend.

The container is provided with a discharge mechanism, which communicateswith a discharge channel extending from the container for discharge ofthe drug formulation to the outlet of the dispenser device. Inembodiments, the discharge channel extends out from a neck of thecontainer.

Typically, the discharge mechanism is provided with a spring mechanism(or other biasing mechanism) that provides a degree of bias that must beovercome in order to allow discharge of drug from the dischargemechanism. Typically, that spring mechanism also acts as a returnmechanism to return the discharge mechanism to its rest state afterfiring thereof.

In embodiments, the discharge channel is received by a cavity or passageprovided to a part (e.g. block form) of the housing, which cavity orpassage enables communication with the outlet for dispensing ofdischarged drug to a patient.

In one embodiment, where the discharge channel is the valve stem of avalved aerosol canister, the valve stem is received within a stem blockprovided to the housing, which stem block includes a passage which actssuch as to channel discharged aerosolized drug from the valve stem tothe outlet.

In another embodiment, where the discharge channel is the discharge tubeof a fluid pump discharge device, the discharge tube is received withina discharge tube block provided to the housing, which discharge tubeblock includes a passage which acts such as to guide discharged fluiddrug from the discharge tube to the outlet.

In one embodiment, the drug discharge device is suitable for dispensingaerosolized drug and thus, generally comprises an aerosol canisterprovided with a discharge valve of the type well-known for use inmetered dose inhaler (MDI) type drug dispensers. The canister isgenerally formed of metal (e.g. aluminium). The valve generally includesa return spring such that once the valve has been fired it is returnedto an ‘at rest’ position ready for subsequent firing thereof.

In a metered dose inhaler (MDI) the discharge device is for dispensingdrug in aerosol form, wherein the drug is comprised in an aerosolcontainer suitable for containing a propellant-based aerosol drugformulation. The aerosol container is typically provided with a meteringvalve, for example a slide valve, which acts as the discharge mechanismfor release of the aerosol form drug formulation to the patient. Theaerosol container is generally designed to deliver a predetermined doseof drug upon each actuation by means of the valve, which can be openedby compressing the valved container, for instance by depressing thevalve while the container is held stationary or by depressing thecontainer while the valve is held stationary.

Where the drug container is an aerosol container, the valve typicallycomprises a valve body having an inlet port through which a drug aerosolformulation may enter said valve body, an outlet port through which theaerosol may exit the valve body and an open/close mechanism by means ofwhich flow through said outlet port is controllable.

The valve may be a slide valve wherein the open/close mechanismcomprises a sealing ring and receivable by the sealing ring a valve stemhaving a dispensing passage, the valve stem being slidably movablewithin the ring from a valve-closed to a valve-open position in whichthe interior of the valve body is in communication with the exterior ofthe valve body via the dispensing passage.

Typically, the valve is a metering valve. The metering volumes aretypically from 10 to 100 μl, such as 25 μl, 50 μl or 63 μl. Inembodiments, the valve body defines a metering chamber for metering anamount of drug formulation and an open/close mechanism by means of whichthe flow through the inlet port to the metering chamber is controllable.Preferably, the valve body has a sampling chamber in communication withthe metering chamber via a second inlet port, said inlet port beingcontrollable by means of an open/close mechanism thereby regulating theflow of drug formulation into the metering chamber.

The valve may also comprise a ‘free flow aerosol valve’ having a chamberand a valve stem extending into the chamber and movable relative to thechamber between dispensing and non-dispensing positions. The valve stemhas a configuration and the chamber has an internal configuration suchthat a metered volume is defined therebetween and such that duringmovement between its non-dispensing and dispensing positions the valvestem sequentially: (i) allows free flow of aerosol formulation into thechamber, (ii) defines a closed metered volume for pressurized aerosolformulation between the external surface of the valve stem and internalsurface of the chamber, and (iii) moves with the closed metered volumewithin the chamber without decreasing the volume of the closed meteredvolume until the metered volume communicates with an outlet passagethereby allowing dispensing of the metered volume of pressurized aerosolformulation.

In embodiments any of the inner parts of the valve (e.g. those which inuse, will contact the drug formulation) are coated with material (e.g.fluoropolymer material) that reduces the tendency of drug to adherethereto. Suitable fluoropolymer materials includepolytetrafluoroethylene (PTFE) and fluorinated ethylene-propyleneco-polymer (FEP). Any movable parts may also have coatings appliedthereto, which enhance their desired movement characteristics.Frictional coatings may therefore be applied to enhance frictionalcontact and lubricants used to reduce frictional contact as necessary.

In another embodiment, the drug discharge device is a fluid dischargedevice suitable for dispensing of fluid drug formulation (e.g.non-pressurised/propellant-free) and thus, generally comprises a fluidcontainer provided with a compression pump. Such pumped dischargedevices are most commonly used in dispensers for dispensing fluid formdrug for nasal delivery.

A suitable fluid discharge device comprises a container for storing afluid to be dispensed having a neck at one end, a compression pumphaving a suction inlet located within the container and a discharge tubeextending out from the neck of the container for transferring said fluidfrom the pump. The pump generally includes a return spring such thatonce the pump has been fired it is returned to an ‘at rest’ positionready for subsequent firing thereof.

A suitable pre-compression pump would be a VP3, VP7 or modifications,model manufactured by Valois SA. Typically, such pre-compression pumpsare typically used with a bottle (glass or plastic) container capable ofholding 8-50 ml of a formulation. Each spray will typically deliver50-100 μl of such a formulation and the device is therefore capable ofproviding at least 100 metered doses.

The container collar is in embodiments in essentially fixed relationshipwith (i.e. it fixes to) the drug discharge device, e.g. the container.In embodiments, the container collar engages (e.g. in essentially fixedrelationship) with a neck of the container.

The container collar may engage with the drug discharge device, e.g.(the neck of) the container, by any suitable permanent or temporaryengagement including a snap-fit engagement mechanism. Preferably, as inthe illustrated embodiments hereinafter, the container collar ispermanently connected to the container through use of a split-ringcollar as described in U.S. patent application Ser. No. 10/110,611(WO-A-01/28887) and US-A-2006/0082039.

There is further provided a transfer element that is arranged tointeract (e.g. directly) with the container collar and is moveable withrespect thereto along the longitudinal axis of the drug dischargedevice. The transfer element may have any suitable form but preferablycomprises an extension collar that is sized and shaped for receipt bythe container and arranged in suitable fashion relative to the containercollar. In one preferred embodiment, the extension collar is sized andshaped for receipt around (i.e. external to) the container collar.

The transfer element includes an actuating portion. The actuatingportion is shaped for interaction with the at least one finger operablemember, and may take any form that facilitates and accommodates thatinteraction including abutment (e.g. flange or shelf), rack and piniongear and indent forms. In embodiments, the actuating portion defines anabutment surface (e.g. a shelf provided thereto).

The housing is provided with the at least one finger operable member.Preferably, the at least one finger operable member is moveabletransversely with respect to the longitudinal axis of the drug dischargedevice. In alternative embodiments, the at least one finger operablemember may therefore directly contact the actuating portion of thetransfer element or be coupled thereto to enable the necessary transferof force.

The at least one finger operable member is in embodiments shaped fordirect interaction with the actuating portion, and may take any formthat facilitates and accommodates that direct interaction includingabutment and indent forms. In embodiments, the at least one fingeroperable member defines a bearing surface arranged for interaction withthe actuating portion of the transfer element.

The term at least one finger operable member is meant to encompass suchmembers operable by action of the finger or thumb, or combinationsthereof of a typical user (e.g. an adult or child patient).

In embodiments, the at least one finger operable member is arranged toapply mechanical advantage. That is to say, the at least one fingeroperable member applies mechanical advantage to the user force to adjust(generally, to enhance or smooth) the force experienced by the transferelement. The mechanical advantage may in one embodiment, be provided ineither a uniform manner such as by a constant mechanical advantageenhancement, for example by a ratio of from 1.5:1 to 10:1 (enhancedforce:initial force), more typically from 2:1 to 5:1. In anotherembodiment, the mechanical advantage is applied in a non-constant mannersuch as progressive increase or progressive decrease of mechanicaladvantage over the applied force cycle. The exact profile of mechanicaladvantage variation may be readily determined by reference to thedesired dispensing performance of the dispenser device.

In embodiments, the at least one finger operable member has a form,which naturally gives rise to mechanical advantage such as a lever.

Preferably, the at least one finger operable member comprises of atleast one lever pivotally connected to part of the housing and arrangedto transfer force to the transfer element (e.g. acting directlythereupon) so as to urge the transfer element in the first directionwhen the or each lever is moved by a user.

In one preferred embodiment, there are two opposing levers, each ofwhich pivotally connect to part of the housing and may be arranged toact upon the transfer element so as to urge the transfer element in thefirst direction when the two levers are squeezed together by a user.

In one embodiment, the movement of the two opposing levers is coupled,which coupling acts to wholly or partly compensate for uneven forcebeing applied in use, by a patient to one lever as applied to the otherlever. Any suitable coupling mechanism may be employed. In oneembodiment, the two opposing levers are provided with meshing teeth,which teeth are arranged to mesh together thereby providing a couplingaction.

In embodiments, the or each lever is pivotally supported at a lower endwithin the housing. By ‘at a lower end within the housing’ it isgenerally meant at that end of the housing which in normal use of thedrug dispenser device by a patient is lowermost.

The use of a lower end pivoted lever configuration has the advantagethat a long lever can be used thereby maximising the mechanical ratiobetween the input force and the force applied to actuate the transferelement. In addition the use of a lever pivotally supported at its lowerend is ergonomically more efficient than using a lever pivotallysupported at an upper end due to the fact that a user will normallygrasp the dispenser device with their thumb positioned close to the endof the lever. With a lever pivotally supported at an upper end (again,relative to the normal ‘in use’ configuration) the location of apatient's thumb is close to the position about which the lever pivotsand hence the maximum leverage is not obtained.

Optionally, there is provided to the drug dispenser device a lockingmechanism for reversibly locking/unlocking the movement of the at leastone finger operable member and/or the container collar. The purpose ofthe locking mechanism is to prevent unintended movement of the at leastone finger operable member and/or container collar and hence, to preventunintended actuation of the dispenser device.

In embodiments, the locking mechanism comprises a locking elementcomprising any suitable limb, protrusion, or abutment which acts such asto interfere with the unintended movement of the at least one fingeroperable member and/or container collar. Such unintended movement mayfor example, arise as a result of patient misuse of the dispenser deviceor during transport of the device (e.g. when carried in the pocket orbag of a patient).

In one embodiment, the locking mechanism is provided to a removeablecover for the outlet (e.g. mouthpiece or nozzle cover). Thus, in use thepatient would remove the outlet cover thereby simultaneously revealingthe outlet and unlocking the locking mechanism. Conversely, after theuse the outlet cover is replaced to again lock the at least one fingeroperable member and/or container collar. In alternative embodiments, thelocking mechanism may comprise an integral part of the removeable coveror by provided as a fixed add-on thereto or be provided as a moveable(e.g. rotatable or translatable) add-on thereto.

In one embodiment, the locking mechanism is arranged to preventunintended movement of the container collar and hence, firing of thedischarge mechanism, but does not impede the movement of the at leastone finger operable member and/or of the transfer element. Thus, whenthe container collar is in its locked state (i.e. locking mechanism isperforming its locking function) the at least one finger operable member(e.g. levers) may still be moved and that movement transfer energy viathe biasing mechanism to move the transfer element, but all movement ofthe container collar is prevented. This form of locking arrangement hasthe advantage that unintended force applied to the finger-operable (e.g.levers) allows for travel thereof without damage thereto or to thedevice as a whole, but without any actuation of the dispenser device(e.g. by firing of the discharge mechanism).

In one embodiment, the container collar is provided at its undersidewith one or more (e.g. two) downward protrusions and the mouthpiece isprovided with a locking mechanism in the form of one or moreinterference elements. In embodiments, the interference element(s) isP-shaped and joined to the mouthpiece by means of a suitable hinge (e.g.living hinge) about which the interference element(s) may rotate. In anembodiment, there are two interference elements joined together by abridge element. When, the mouthpiece engages with the body of thedispenser device (i.e. in the mouthpiece-closed position) theinterference element(s) abuts the downward protrusion(s) to therebyprevent (i.e. lock) any downward movement of the container collar.Unintended movement of the container collar and hence, unintendedactuation of the dispenser device (i.e. firing of the dischargemechanism) is hence prevented. In embodiments, however the at least onefinger operable member and transfer element are free to move, even whenthe container collar is in its locked state.

One particular locking mechanism, in which one or more rotatableinterference elements are provided to the mouthpiece, is described inApplicant's co-pending PCT Patent Application No. WO-A-2007/028992 whichclaims priority from UK patent application no. 0518355, eachincorporated herein by reference.

There is further provided (e.g. to the container collar) a pre-loadmechanism to prevent transfer of actuation force from the transferelement to the container collar to (i) move said discharge device alongthe longitudinal axis in the first direction to actuate the dischargemechanism, and optionally also (ii) to actuate any actuation counteruntil a pre-determined threshold force is overcome.

Thus, initially as the transfer element is provided with actuation forcein the direction of the longitudinal axis in response to patientactuation of the at least one finger operable member the pre-determinedthreshold force is experienced. Once however, the pre-determinedthreshold force as defined by the pre-load mechanism is exceeded, theactuation force is released and the transfer element is thereby,propelled along the longitudinal axis in the first direction in drivingrelationship with the container collar to drive the container collar(and hence the discharge device) in the first direction to actuate thedischarge mechanism resulting in discharge of drug formulation throughthe discharge channel and to the outlet for delivery to the patient.

In other words, the pre-load mechanism acts such as to prevent actuationof the discharge mechanism of the drug discharge device until apre-determined threshold force is applied to the at least one fingeroperable member. The pre-determined threshold force might thus, bethought of as a ‘barrier’ force which must first be overcome before theactuation force may be released to actuate the discharge mechanism. Inessence, the pre-load mechanism acts as a ‘commitment’ feature, whichallows release of actuating force/energy to the dispensing mechanismonly when the ‘barrier’ force has been exceeded.

The quantum of pre-determined force that is to be overcome beforeactuation of the discharge mechanism is enabled is selected according tovarious factors including the typical user profile, nature of the drugformulation and the desired discharge characteristics.

Typically, the pre-determined threshold force is in the range from 5 to40N, more typically from 10 to 30N (e.g. 15N). That is to say, typicallyfrom 5 to 40N, more typically from 10 to 30N (e.g. 15N) of force must beapplied by the patient to overcome the pre-determined threshold beforeactuation of the discharge mechanism is enabled. Such values tend tocorrespond to a force which prevents a suitable ‘barrier force’ to aweak, nondescript or unintended finger movement whilst readily beingovercome by the determined finger (or thumb) action of a user. It willbe appreciated that if the device is designed for use by a child orelderly patient it may have a lower pre-determined force than thatdesigned for adult usage.

In embodiments, the pre-load mechanism is interposed between thecontainer collar and the housing.

In embodiments, the pre-load mechanism comprises one or more detentsformed on the container collar for engagement with part of the housing,the or all of the detents being disengageable from the housing when thepre-determined threshold force is applied to the transfer element viathe at least one finger operable member so as to allow the containercollar to move along the longitudinal axis in such a way that thedischarge mechanism is actuated.

Preferably, each detent comprises a flexible (e.g. resilient) supportlimb, such as a support leg which engages (e.g. latches to) a step orabutment provided to the housing. When the pre-determined thresholdforce is overcome, the or each flexible support limb disengages from thestep or abutment to allow the container collar to move along thelongitudinal axis such that the discharge mechanism is actuated. Inembodiments, the or each support limb is provided to the lower end ofthe container collar (i.e. that end which is closest to the outlet). Anarrangement of from two to four (e.g. three) flexible support limbs isparticularly preferred. Alternatively, the or each support limb may havea hinged or articulated form.

In embodiments, a guide mechanism is provided to the transfer element(e.g. extension collar) to guide the disengagement of the flexiblesupport limb from its respective step or abutment on the housing.Preferably, such guide mechanism comprises a guide ramp, which interactswith a shaped head of each flexible support limb.

In embodiments, a reseat guide mechanism is provided to the transferelement (e.g. extension collar) to guide the re-engagement of theflexible support limb with its respective step or abutment on thehousing. Preferably, such reseat guide mechanism comprises a reseatguide ramp, which interacts with a shaped reseat head of each flexiblesupport limb.

In embodiments the ‘disengagement’ guide mechanism (e.g.) ramp interactswith an outer shaped head of each flexible support limb and the‘re-engagement’ reseat guide mechanism (e.g. ramp) interacts with aninner shaped reseat head of each flexible support limb.

Alternatively, the pre-load mechanism may comprise of one or moredetents formed on the housing for engagement with part of the containercollar, the or all of the detents being disengageable from the containercollar when the pre-determined threshold force is applied to thetransfer element via the at least one finger operable member so as toallow the discharge mechanism to be actuated.

For effective actuation of the discharge mechanism (e.g. valve or pump)of the drug discharge device the actuating force must be sufficient toboth overcome the pre-determined force of the pre-load mechanism and toactuate that discharge mechanism. Thus, for example where the dischargemechanism comprises a valve or pump having a return spring, theactuating force should be sufficient to overcome that return spring toreliably fire the valve or pump.

It is desirable that the actuating force, which is applied by thepatient to the at least one finger operable member be kept to a minimum.Desirably also, the overall size of the device is kept relatively small(e.g. fits comfortably in the patient's hand) from both an ergonomicsand aesthetics standpoint.

There is further provided a biasing return mechanism, which connects thecontainer collar to the transfer element. The biasing return mechanismacts to store biasing return energy on moving the transfer elementrelative to the container collar along the longitudinal axis in thefirst direction, and in the absence of actuating force acts such as tomove (‘reset’) the transfer element back to its initial positionrelative to the container collar.

In embodiments, the biasing return mechanism comprises one or moresprings (e.g. extension springs) or other resiliently compressible orexpandable mechanical members for storing mechanical energy. Preferably,the biasing mechanism comprises an arrangement of two springs locatingone on either side of the container collar (i.e. at a 180° radialspacing).

The drug dispenser herein optionally includes an actuation counter. Theactuation counter suitably includes a mechanism for registering anddisplaying dose count information to the patient. Suitably, that dosecount information relates to the number of doses of drug delivered fromor remaining in the dispenser device. The information may be delayed indigital or analogue form, typically using standard count indicia (e.g.‘999’ to ‘000’ indicia count display). Embodiments involving either‘counting up’ or ‘counting down’ in increments are envisaged.

The pre-load mechanism herein acts such as to prevent transfer ofactuating force to the container collar to actuate the actuation counteruntil a pre-determined threshold force is overcome. Thus, a count isregistered by the actuation counter only in response to a user actuationthat is sufficient to overcome the ‘barrier’ force provided by thepre-load mechanism and which thereby results in dispensing of a dosefrom the drug container.

In embodiments, the actuation counter is actuable in response tomovement of the container collar or of the container along thelongitudinal axis in the first direction.

In embodiments, the actuation counter is actuable in response to drive(e.g. engageable drive) interaction with a driver element provided tothe container collar or container. The driver element may for example,take the form of a protrusion (e.g. tooth), an abutment, an indent or aslot provided to the container collar or container.

In embodiments, the actuation counter is actuable in response to driveinteraction with a driver element provided to a drive feature connectingto the container collar or container. The driver element may forexample, take the form of a protrusion (e.g. tooth), an abutment, anindent or a slot provided to the drive feature. In embodiments, thedrive feature comprises a plate connecting to the container collar.

The actuation counter may adopt any suitable form. The actuation counteris in embodiments sized and shaped for effective receipt by the housingof the drug dispenser.

In embodiments, the actuation counter is supplied as an assembly forinsertion into the drug dispenser.

In embodiments, an inner wall of the housing of the drug dispenser actsas a mounting for some or all of the parts of the actuation counter.

In embodiments, the actuation counter comprises one or more count wheelsprovided with count indicia thereon for display of the actuation count.

In an embodiment, the actuation counter comprises:

a first count wheel arranged to rotate about a first axis of rotation,said first count wheel including one or more drive receipt elementsarranged thereon for receipt of drive for drivable rotation of the firstcount wheel about said first axis of rotation;

a second count wheel arranged to rotate about the first axis ofrotation, said second count wheel including a set of teeth arrangedannularly thereon; and

a kick wheel arranged to rotate about a second axis of rotation offsetfrom the first axis of rotation, said kick wheel including a set of kickteeth arranged annularly thereon and in meshed relationship with the setof teeth of the second count wheel such that rotary motion of the kickwheel results in rotary motion of the second count wheel,

wherein said first count wheel further includes at least one fixed indextooth arranged for intermittent meshing with the kick teeth of the kickwheel such that rotary motion of the kick wheel results from rotarymotion of the first count wheel only when said intermittent meshingoccurs.

In embodiments, the preferred actuation counter is configured andarranged so that said intermittent meshing is able to occur a pluralityof times.

By ‘arranged annularly’ herein it means arranged about a common radius(i.e. defining an annular arrangement).

The first or second count wheel may for example, take the form of a discor a ring.

The drive receipt elements can take any suitable form including one ormore teeth and/or indents. In embodiments, the drive receipt elements ofthe first count wheel are arranged annularly, such as about an inner orouter circumferential wall of the first count wheel.

In one embodiment, the one or more drive receipt elements of the firstcount wheel comprise a set of teeth arranged annularly thereon fordrivable rotation of the first count wheel about the first axis ofrotation. Drive of the teeth is in embodiments provided by a driverelement provided to another part of the drug dispenser. In embodiments,the driver element is provided to the container collar or container orto a drive feature connecting to the container collar or container.

In another embodiment, the preferred actuation counter is provided witha ratchet, and the one or more drive receipt elements of the first countwheel comprise one or more ratchet drive receipt elements arrangedthereon for receipt of drive from said ratchet to rotate the first countwheel about said first axis of rotation.

The ratchet is in embodiments a ratchet wheel arranged for rotationabout an axis, which is preferably common with the first axis ofrotation about which the first count wheel rotates. The ratchet is inembodiments provided with one or more ratchet drive elements such as oneor more ratchet drive tongues.

In embodiments, the ratchet is itself provided with one or more drivereceipt elements for receipt of drive that results in movement (e.g.rotation) of the ratchet. Such drive receipt elements can take any formincluding one or more teeth, protrusions and/or indents. Drive of thedrive receipt elements of the ratchet is in embodiments provided by adriver element provided to another part of the drug dispenser. Inembodiments, the driver element is provided to the container collar orcontainer or to a drive feature connecting to the container collar orcontainer.

In a preferred embodiment, the first count wheel is provided with acircular cavity (e.g. hollowed out portion) sized and shaped for receiptof the ratchet wheel. The ratchet drive receipt elements are arrangedabout the inner circumferential wall (i.e. about the periphery) of thecavity for suitable ratchet drive interaction with the ratchet wheel.

Alternatively, the first count wheel takes the form of a ring that issized and shaped for disposed receipt of the ratchet wheel. The ratchetdrive receipt elements are arranged circumferentially about (i.e. aboutthe periphery of) the inner wall of the ring for suitable ratchet driveinteraction with the ratchet wheel.

In embodiments, the first and second wheels may be arranged to rotate inthe same direction or in opposing directions (i.e. one clockwise and oneanti-clockwise).

The second count wheel includes a set of teeth arranged annularly (e.g.circumferentially) thereon. The teeth are therefore arranged in annularfashion at or about the circumference of the second count wheel.

In embodiments, the second count wheel is arranged concentric to thefirst count wheel. In one embodiment, the second count wheel takes theform of a ring and the first count wheel (e.g. disc or ring shape) issized and shaped for receipt within the ring. The diameter of the firstcount wheel is therefore typically slightly less than that of the innerdiameter (i.e. the ring hole diameter) defined by the ring-shaped secondcount wheel.

In one embodiment, the first and second count wheels are arrangedconcentrically and at the same level (i.e. they share the same plane ofrotation).

In another embodiment, the first and second count wheels are arrangedconcentrically and at different levels (i.e. with different planes ofrotation).

In embodiments, the plane of rotation of the second counter wheel isslightly raised relative to that of the first counter wheel. In oneembodiment, the second count wheel is provided with a protrusion that inuse, extends over and above part of the first count wheel and that maytherefore function to shutter off part of the first count wheel.

The kick teeth are preferably arranged in annular fashion at or aboutthe circumference of the kick wheel.

As the kick wheel is rotated the meshing of the kick teeth thereof withthe teeth of the second count wheel results in rotation of the secondcount wheel.

The first count wheel further includes at least one fixed index tootharranged for intermittent meshing with the kick teeth of the kick wheel.That is to say, the at least one index tooth is fixed to the first countwheel and may be brought into meshed relationship with the kick teeth ofthe kick wheel on an intermittent basis.

Rotary motion of the kick wheel results from rotary motion of the firstcount wheel only when said intermittent meshing of the at least oneindex tooth with the kick teeth occurs. When meshing occurs, a contactratio of 1 between the at least one index tooth and the kick teeth ispreferred, although other whole integer (2, 3 . . . ) contact ratios maybe used.

Typically, the at least one index tooth is fixed at a point at or aboutthe circumference of the first count wheel. Rotation of the first countwheel is then arranged to bring the at least one index tooth into meshedrelationship with the kick teeth of the kick wheel at a particular pointof the rotary cycle of the first count wheel. It may be therefore beappreciated that in this case, meshing occurs once during each completerotation of the first count wheel.

In embodiments, either one or both counter wheels interact with areverse rotation (e.g. ratchet) mechanism to prevent reverse movement ofthe counter wheels.

In embodiments, some or all gear teeth of some or all of the toothedparts herein have flanged form to enable effective meshing togetherthereof.

In embodiments, the actuation counter includes a counter housing, whichhouses some or all of the other elements of the actuation counter. Inembodiments, the counter housing is defined at least in part by thehousing of the drug dispenser.

In embodiments, the counter housing is shaped to define the first axisof rotation and the second axis of rotation. In embodiments, the firstcount wheel mounts to the counter housing for rotation about the firstaxis of rotation and the kick wheel mounts to the counter housing forrotation about the second axis of rotation.

In embodiments, the counter housing includes a viewing window throughwhich the count may be viewed. In embodiments, the counter housingincludes a bezel and/or lens cover for the count wheels and throughwhich indicia of the count wheels are generally visible.

In one embodiment, a shutter is provided to close off the viewing windowat a predetermined point in the actuation counter operation,particularly at the ‘end of life’ of the drug product, which typicallycorresponds to the point at which all doses in the normal (prescribed)delivery cycle have been provided. In embodiments, the shutter may beprovided as a separate element of the actuation counter or drugdispenser or be formed as an integral part of the second counter wheel,as described hereinbefore.

In embodiments, the first and second count wheels are adapted in use torotate in the same sense about the first axis.

In embodiments, the drug dispenser has a display region through whichthe first and second count wheels are rotatable and a shutter which ismovable to a shuttering position in which it shutters the displayregion. In embodiments, the actuation counter is so configured andarranged that the shutter is only movable to the shuttering positionwhen the first and second count wheels are in predetermined angularpositions about the first axis. In embodiments, the actuation counter isconfigured and arranged so that the shutter is only able to be moved tothe shuttering position when the first count wheel has rotated through aplurality of revolutions about the first axis. In embodiments, theactuation counter is configured and arranged such that the shutter movesto its shuttering position in response to movement of at least one ofthe count wheels.

In embodiments, the shutter is moved to its shuttering position by theat least one count wheel. In embodiments the shutter is carried to theshuttering position by the at least one count wheel. In embodiments, theat least one count wheel is the second count wheel. In embodiments, theat least one count wheel and the shutter have cooperating parts throughwhich, in use, the at least one count wheel moves the shutter to itsshuttering position.

In embodiments, the actuation counter is configured and arranged todisplay a count sequence with the count wheels and to cause the shutterto move to its shuttering position at the end of the count sequence.

In embodiments, the shutter is comprised in one of the count wheels. Inembodiments, the count wheel is integrally formed with the shutter. Inembodiments, the shutter overlies the other count wheel. In embodiments,the shutter is comprised in the second count wheel.

In embodiments, the actuation counter is configured and arranged tosequence from a count mode of operation, in which the first count wheelis able to drive rotation of the second count wheel through the kickwheel, to a non-count mode of operation, in which the first count wheelis unable to drive rotation of the second count wheel through the kickwheel. In embodiments, the actuation counter is arranged to sequencefrom the count mode to the non-count mode when the first count wheel hascompleted a predetermined number of revolutions about the first axis. Inembodiments, the actuation counter is adapted to sequence from the countmode to the non-count mode when the second count wheel is disposed in apredetermined angular orientation about the first axis.

In embodiments, the actuation counter is configured and arranged suchthat in the non-count mode meshing of the kick teeth with the at leastone index tooth and/or the second count wheel teeth is unable to occur.In embodiments, a gap is provided in the set of kick teeth or the secondcount wheel teeth to disable meshing in the non-count mode.

In an embodiment of the invention, the actuation counter is a dosecounter for counting the number of doses of drug dispensed from the drugdispenser device and comprises first and second count wheels which areconcentrically arranged for rotation on a common axis of rotation, eachcount wheel having count indicia thereon; a display region positionedfor the count indicia of each count wheel to register with and displaythe count of the counter; a ratchet for incrementally rotating the firstcount wheel in a predetermined sense to change the count indicia thereofregistering with the display region; and a mechanism adapted tointermittently transmit the incremental rotation of the first countwheel into an incremental rotation of the second count wheel in apredetermined sense to change the count indicia thereof registering withthe display region.

Embodiments are envisaged in which the drug discharge device isreversibly removable from the housing of the drug dispenser device. Insuch embodiments the drug dispenser device comprises a housing assemblyand a drug discharge device receivable thereby.

According to another aspect of the present invention there is thereforeprovided a housing assembly according to claim 128.

According to a still further aspect of the present invention there isprovided a kit of parts comprising a housing assembly as described aboveand a drug discharge device receivable thereby. The drug dischargedevice has a longitudinal axis and comprises a container for storing adrug formulation to be dispensed, a discharge mechanism and a dischargechannel extending from said container for discharge of said drugformulation.

It is also envisaged that the housing assembly could be supplied as aseparate item, into which a user or pharmacist later fits a suitabledrug discharge device.

In a yet further aspect of the invention there is provided a drugdispenser device according to claim 45.

The drug dispenser device comprises a housing which comprises an outletfor insertion into a body cavity of a patient.

The drug discharge device may be disposed in the housing such that thedischarge mechanism is held stationary and the container is movable in afirst direction relative to the discharge mechanism to put the device ina discharge mode where the formulation is discharged from the containerto the outlet.

There is provided a transfer (or loading) arrangement for transferringthe container in the first direction relative to the discharge mechanismcomprising a first part attached to the container, a second partconnected to the first part so that the first and second parts aremovable towards and away from each other, a return biasing forcemechanism for biasing the first and second parts to a restingconfiguration thereof, a latch adapted in use to latch the first partagainst movement in the first direction, and a latch release adapted forreleasing the latch, when an actuating force of greater than apre-determined threshold force is applied to the second part in thefirst direction, to enable the actuating force to move the first part inthe first direction and carry the container in the first directionrelative to the discharge mechanism to put the drug discharge device inits discharge mode.

An actuation counter is optionally configured and arranged to beactuated by movement of the first part or the container in the firstdirection on release of the latch.

The latch may be provided on the first part and the latch release may beprovided on the second part. The first part may be a collar. The secondpart may be a collar, for instance of annular form. The latch may beformed by one or more projections of the first part. The latch releasemay be formed by a surface thereof for contacting the latch for releasethereof. The return biasing force may be provided by a resilientelement, typically a spring. The device may have an actuating mechanismfor moving the second part of the transfer (loading) arrangement in thefirst direction the predetermined distance from the first part for thelatch release to release the latch. The actuating mechanism may compriseat least one finger operable member, for instance one or more levers,such as in the embodiments hereinafter to be described with reference tothe drawings.

According to a further aspect of the invention there is provided aloading arrangement for loading a fluid dispensing container into adispensing mode thereof, comprising:

a first part for attachment to the container;

a second part movable in a first direction;

a latch adapted in use to latch the first part against movement in thefirst direction; and

a latch release adapted for releasing the latch, when the second parthas moved a predetermined distance from the first part in the firstdirection,

wherein the first and second parts are provided with co-operable drivefeatures adapted in use to engage after the latch is released so thatthe second part is able to drive the first part in the first directionfor placing the fluid dispensing container into its dispensing mode.

In an embodiment of the invention, such as in the illustratedembodiments, the second part may only be able to move the predetermineddistance from the first part upon application of a predetermined forcethereto. The application of the predetermined force causes the secondpart to continue to move in the first direction after release of thelatch so as to drive the first part in the same direction through thedrive features.

The second part may be connected to the first part, for example througha biasing mechanism (e.g. one or more biasing elements, such assprings).

An actuation counter may be configured and arranged to be actuated bymovement of the first part or the container in the first direction onrelease of the latch.

The latch may be provided on the first part and the latch release may beprovided on the second part. The predetermined force may thus be theforce required to be applied for the latch to be released. The firstpart may be a collar. The second part may be a collar, for instance ofannular form. The latch may be formed by one or more projections of thefirst part. The latch release may be formed by a surface of the secondpart for contacting the latch for release thereof.

The fluid dispensing container may comprise a container part for afluid, suitably a fluid drug formulation, and to which the first part isattached, and a dispensing member through which fluid inside thecontainer part is dispensible therefrom on movement of the containerpart relative to the dispensing member (the “dispensing mode”). Thedispensing member may be a valve stem of a valve or a pump stem of apump. In use, when the latch release releases the latch, the first part(driven by the second part) is able to move the container part relativeto the dispensing member when this is held stationary, e.g. in a supporttherefor in a drug dispenser, such as a stem/nozzle block in a metereddose inhaler (MDI) actuator.

In another aspect of the invention there is provided an assembly of afluid dispensing container and the loading arrangement of the invention,the first part being attached to the container.

In a yet further aspect of the invention there is provided a drugdispenser having a housing which receives the assembly of the invention,the container comprising the container part and the dispensing member,the housing having a support which receives the dispensing member and alatching surface for the latch to latch to to latch the first part, andhence the container part, against movement in the first direction, andthe dispenser having an outlet through which fluid dispensed from thecontainer part is dispensible from the dispenser and an actuatingmechanism for moving the second part of the loading arrangement in thefirst direction the predetermined distance from the first part for thelatch release to release the latch from the latching surface and for thesecond part to drive the first part in the first direction andconsequently move the container part in the first direction relative tothe dispensing member for dispensing therefrom through the outlet.

The actuating mechanism may comprise at least one finger operablemember, for instance one or more levers, such as in the embodimentshereinafter to be described with reference to the drawings.

The drug dispenser device of the invention is suitably an inhaler, moresuitably of the well-known “metered dose inhaler” (MDI) type, and yetmore suitably a hand-held, hand-operable breath-coordinated MDI. In sucha MDI, the patient manually actuates the MDI for release of the drugfrom the drug discharge device while concurrently inhaling at theoutlet. Thus inhalation and actuation are coordinated. This is indistinction from breath-operated MDIs, where the inhalation event itselfactuates the MDI so that no coordination is required.

Additional aspects and features of the present invention are set forthin the claims and in the description of exemplary embodiments of thepresent invention which now follow with reference to the accompanyingFigures of drawings. Such exemplary embodiments may or may not bepracticed mutually exclusive of each other, whereby each embodiment mayincorporate one or more features of one or more of the otherembodiments. It should be appreciated that the exemplary embodiments areset forth to illustrate the invention, and that the invention is notlimited to these embodiments.

FIG. 1 shows a perspective view of a hand-held, hand-operable, breathcoordinated drug dispenser device of the MDI type herein in the ‘atrest’ position;

FIG. 2 shows a perspective view of the drug dispenser device of FIG. 1with upper front cover part, front plate, mouthpiece and mouthpiececover removed and the lower front cover part shown in cut-away section,the device again being shown in the ‘at rest’ position;

FIGS. 3 a to 3 b show front views of the drug dispenser device of FIG. 1with upper front cover part and front plate removed and the left lowerfront cover part and left-side of mouthpiece shown in cut-away section,the device respectively being shown in ‘at rest’ and second stage ofactuation positions;

FIGS. 4 a to 4 c show front views of the drug dispenser device of FIG. 1with upper front cover part, front plate and left lever removed and theleft lower front cover part and left-side of mouthpiece shown incut-away section, the device respectively being shown in third, fourthand fifth stages of actuation positions;

FIG. 5 shows an exploded view of part of the internal mechanism of thedrug dispenser device of FIG. 1;

FIGS. 6 a to 6 e show sectional side views of interaction of thecontainer collar and extension collar parts of the dispenser device ofFIG. 1 during sequential operational steps of the internal mechanism asshown in FIG. 5;

FIG. 7 shows a schematic scrap view of the drug dispenser device of FIG.1 to reveal part of the internal mechanism and in particular, the‘interlock’ mechanism provided to block actuation thereof when themouthpiece is covered by the mouthpiece cover;

FIG. 8 shows a perspective view of the drug dispenser device of FIG. 1with the mouthpiece cover removed from the mouthpiece and thus, in a‘ready to use’ position;

FIG. 9 shows a perspective view of the drug dispenser device of FIG. 1with the mouthpiece cover removed from the mouthpiece and the leversdepressed and thus in the ‘in use’ position;

FIG. 10 illustrates a perspective view of a first half of the drugdispenser of FIG. 1 showing air flow into the housing in the ‘in use’position thereof;

FIG. 11 illustrates a perspective cut-away view of a second half of thedrug dispenser device of FIG. 1 (with actuation counter and details ofinternal mechanism omitted) showing air flow through the chambers of thehousing in the ‘in use’ position thereof;

FIG. 12 illustrates a perspective cut-away view of a second half of adrug dispenser device that is a slight variation of that drug dispenserdevice of FIG. 1 (with actuation counter and details of internalmechanism omitted) showing air flow through the inhaler body in the ‘inuse’ position thereof;

FIG. 13 shows an exploded view of an actuation counter herein arrangedfor receipt within the front upper housing part of the first drugdispenser of FIG. 1 or second drug dispenser device of FIG. 12;

FIGS. 14 a and 14 b respectively show underside and top views of theactuation counter of FIG. 13;

FIGS. 15 a and 15 b show cut-away views of the actuation counter of FIG.13 at respectively ‘count 120’ and ‘count 119’ positions;

FIGS. 16 a and 16 b respectively show cut-away views corresponding toFIGS. 15 a and 15 b of the actuation counter of FIG. 13 absent thedecimals count wheel;

FIGS. 17 a and 17 b respectively show cut-away views corresponding toFIGS. 15 a and 15 b of the actuation counter of FIG. 13 absent thenumerals count wheel;

FIGS. 18 a and 18 b show cut-away views of the actuation counter of FIG.13 at respectively ‘count_(—)0’ and ‘shuttered’ positions;

FIGS. 19 a and 19 b respectively show cut-away views corresponding toFIGS. 18 a and 18 b of the actuation counter of FIG. 13 absent thenumerals count wheel;

FIG. 20 shows a front view of the drug dispenser device of FIG. 1 withupper front cover part and actuation counter removed, the device beingin the ‘at rest’ position;

FIG. 21 shows a perspective view of the drug dispenser device of FIG. 1with the upper front cover part and actuation counter disposed thereinshown detached from the remainder of the device, the device being shownin a ‘at rest’ position;

FIG. 22 shows a plan view of the inner side of the upper front coverpart of the drug dispenser device of FIG. 1 and showing the actuationcounter disposed therein;

FIG. 23 shows a perspective view from above of the lower housing partand mouthpiece assembly (shown separated) of the drug dispenser deviceof FIG. 1;

FIGS. 24 a and 24 b show an alternative ‘two part form’ lower housingpart, as respectively shown separated and as assembled, for use with thedrug dispenser device of FIG. 1;

FIGS. 25 a to 25 n respectively show front views of mouthpiece forms,which may be employed in the drug dispenser devices of FIG. 1 or 12 asan alternative to the mouthpieces thereof.

Turning now to the drawings, FIG. 1 shows a drug dispenser device 1herein which is in the form of a hand-held, hand-operable, breathcoordinated pressurised metered dose inhaler (MDI). This type of devicerequires a patient to coordinate their inhalation at a dispensing outletof the device (in this embodiment, a mouthpiece 14) with manualactuation of the device so that the inhalation is coordinated withrelease of drug from the device so that drug is entrained by theinhalation airflow to the target location in the respiratory tract (inthis case, the lungs) of the patient.

The device 1 comprises a housing defined in combination by front 10 aand rear 10 b upper housing parts and lower housing part 12, all ofwhich are, in this embodiment, formed from plastic. It will be notedthat the overall form of the housing is arranged for ease of receipt bya user's hand such that in general terms the rear of lower housing part12 is received by the user's palm. Mouthpiece 14 (not visible in FIG. 1,but see FIG. 3 a) is protected by removeable mouthpiece cover 16, andextends from the front of lower housing part 12 and is arranged in use,for insertion into the mouth of a patient for inhalation therethrough.

A ledge 13 a, 13 b is provided to the base of the lower housing part 12such that the device may be arranged to ‘stand upright’ on the ledges 13a, 13 b and mouthpiece cover 16, when cover 16 covers the mouthpiece 14.When the cover 16 is moved to its ‘mouthpiece uncovered’ position, thedevice is able to ‘stand upright’ on the end face 16 a of the cover 16itself (see FIG. 8).

A viewing window 216 is provided to the front upper housing part 10 afor viewing of count indicia displayed by a counter 201 locating withinthat part 10 a and described in more detail hereinafter with referenceto FIGS. 13 to 22.

Opposing levers 20 a, 20 b protrude from apertures 11 a, 11 b providedto the front 10 a and rear 10 b upper housing parts. The levers 20 a, 20b are shaped such as to respectively accommodate the finger and thumb ofa patient in use, thereby facilitating one-handed operation of thedevice.

FIG. 23 shows the lower housing part 12 and mouthpiece 14 (shownseparated from each other, in this view) of the drug dispenser device ofFIG. 1. Provided to the lower housing part 12 is stem block 8, which isarranged to receive valve stem 7 of an aerosol canister 5 (see alsoFIGS. 3 a and 5). The stem block 8 also includes a passage 9, which inuse acts such as to guide discharged aerosolized drug from the valvestem 7 to the mouthpiece 14. Step portions 18 a, 18 b, 18 c, the purposeof which will be described in more detail in the later description, arealso provided.

FIGS. 24 a and 24 b show an alternative ‘two part form’ lower housingpart 412, as respectively shown separated and as assembled, for use withthe drug dispenser device of FIG. 1 as an alternative to the lowerhousing part 12 of FIG. 23. This two part form comprises lower housingpart 412, which is arranged to receive separate stem block part 490.That separate stem block part 490 includes stem block 408 and stem blockpassage 409. As before, the lower housing part defines step portions 418a, 418 b, 418 c. During assembly the separate parts 412, 490 are broughttogether and sockets 494 a, 494 b, 494 c on the stem block part 490aligned with posts 492 a, 492 b, 492 c on the lower housing part. Theparts 412, 490 are then joined to each other by means of heat welding(‘heat staking’) at each respective post 492 a, 492 b, 492 c to socket494 a, 494 b, 494 c mating point. Advantages of using the alternative‘two part form’ lower housing part 412 and stem block part 490 assemblyare that the precision features of the stem block part 490 are easier toproduce and inspect. The stem block part 490 is generally made from apolymer selected for ease of drug delivery. The lower housing part 412is in embodiments, formed of ABS.

Details of the inner workings of the device 1 of FIG. 1 may beappreciated by reference to FIG. 2, in which the upper 10 a fronthousing part and mouthpiece cover 16 have been removed. It will be seenthat each opposing lever 20 a, 20 b pivotally connects to the upperhousing part 10 a, 10 b by means of pivot connector 22 a, 22 b. Thepositioning of the pivotal connection is selected to facilitate thedesired finger-thumb operability of the levers 20 a, 20 b by a squeezingmovement. It will also be seen that the lower ends 21 a, 21 b of eachlever 20 a, 20 b are geared such as to mesh together, thereby tending tothe couple the motion of each respective lever 20 a, 20 b one to theother.

Although not shown, each lever 20 a, 20 b has a lower end 21 a, 21 b oneither side thereof providing a generally U-shape to each lever 20 a, 20b.

Provided to the housing, but partially obscured from view by containercollar 30, there is provided a drug discharge device, which takes theform of cylindrical valved aerosol canister 5 of the type commonly knownfor use in an MDI. The valve stem 7 of the drug discharge device (seealso FIGS. 3 a, 3 b and 5) is received within the stem block 8 providedto the housing, which stem block 8 includes the passage 9 which actssuch as to guide discharged aerosolized drug from the valve stem to themouthpiece 14.

The levers 20 a, 20 b are arranged in the device such that the lowerends 21 a, 21 b of each lever 20 a, 20 b are disposed on opposing sides(front and rear) of the drug discharge device.

In this embodiment, and particularly referring to FIG. 5, the canister 5has a body 6 made of metal, for instance of stainless steel or, morepreferably, of aluminium or an aluminium alloy. The canister contains apressurised drug aerosol formulation. The formulation comprises the drug(one or more drug actives) and a fluid propellant, and optionally one ormore excipients and/or adjuvants. The drug is in solution or suspensionin the formulation. The propellant is typically a CFC-free propellant,suitably a liquid propellant, and preferably is a HFA propellant, suchas HFA-134a or HFA-227 or a combination thereof. The drug active(s) istypically of the type for use in treatment of a respiratory disease orcondition, such as asthma or chronic obstructive pulmonary disease(COPD). The active(s) may also be for prophylaxis or palliation of arespiratory disease or condition.

The canister 5 may have its inner surface coated with a fluorocarbonpolymer, optionally in a blend with a non-fluorocarbon polymer, such asa blend of polytetrafluoroethylene and polyethersulphone (PTFE-PES), asdisclosed in U.S. Pat. Nos. 6,143,277; 6,511,653; 6,253,762; 6,532,955;and 6,546,928. This is particularly preferred if the drug is insuspension in the formulation, and especially if the suspensionformulation is composed only, or substantially only, of the drug and HFApropellant.

The valve stem 7 forms part of a metering valve (not shown) mounted inthe canister 5, as will be understood by the skilled person in the art,and as commercially available from manufacturers well known in theaerosol industry, for example, from Valois, France (e.g. DF10, DF30,DF60), Bespak plc, UK (e.g. BK300, BK356, BK357) and 3M-Neotechnic Ltd,UK (e.g. Spraymiser™). The metering chamber of the metering valve may becoated with a fluorinated polymer coating, such as formed fromperfluoro-hexane, for instance by cold plasma polymerisation, asdetailed in US-A-2003/0101993.

As may be further understood with reference also to FIG. 5, which showsan exploded view of key parts of the internal mechanism, the containercollar 30 permanently engages via split-ring collar 33 with the neck 5 aof the canister 5 such that the so-engaged parts are moveable togetherrelative to the housing in a direction defined by the longitudinal axisL-L of the canister 5 (i.e. generally up and down when the device 1 isupright). The split-ring collar 33 permanently engages the containercollar 30 to the canister 5 as described in U.S. patent application Ser.No. 10/110,611 (WO-A-01/28887) and US-A-2006/0082039.

With reference now also to FIGS. 6 a to 6 e, the container collar 30connects via closed coil extension return springs 50 a, 50 b andrespective spring connection points 31 a, 31 b and 41 a, 41 b toextension collar 40, which is provided at its lower end with outer ramps44 a, 44 b, and also with inner ramps 43 a, 43 b. This multi-collararrangement is such that the extension collar 40 is moveable withrespect to the container collar 30 along the longitudinal axis L-L ofthe drug discharge device.

The springs 50 a, 50 b will typically be formed of metal, for instancestainless steel, such as 302 grade stainless steel.

The extension collar 40 includes an actuating portion in the form ofshelf 42, which is arranged for interaction with the lower ends 21 a, 21b of the opposing levers 20 a, 20 b such that when the levers aresqueezed together (i.e. inwards relative to the housing) the shelf 42and hence, extension collar 40 are pushed downwards. The containercollar 30 is further provided with flexible support legs 34 a, 34 b,which act to provide a pre-load mechanism to prevent transfer of theactuating force to the container collar 30 to move the canister 5downwards along the longitudinal axis L-L to actuate the valve thereof(and hence, to fire the aerosolized drug dose) until a pre-determinedthreshold force is overcome. Each flexible support leg 34 a, 34 b isarranged for interaction with a respective step 18 a, 18 b on thehousing. Each flexible support leg 34 a, 34 b is also provided with aprotruding inner foot 35 a, 35 b and protruding outer foot 36 a, 36 b,the purpose of which will become clearer from the later description.

In the ‘at rest’ position of FIGS. 2, 3 a and 6 a, the bottom of eachflexible support leg 34 a, 34 b is slightly spaced from its respectivestep 18 a, 18 b on the housing. The container collar 30 is furtherprovided with downward protrusions 38 a, 38 b, the purpose of which willalso become clear from the later description. In embodiments, a thirdflexible support leg (not visible, but associated with third step 18 cas visible on FIG. 23) locates at the rear of the container collar.

In general operational terms, referring now also to FIG. 3 a, theopposing levers 20 a, 20 b are moveable inwardly, transversely withrespect to the longitudinal axis H-H of the housing, to apply anactuating force to the shelf 42 of the extension collar 40 to move theextension collar 40 downwards along that longitudinal axis (i.e. towardsstem block 8 and mouthpiece 14).

The flexible support legs 34 a, 34 b act to provide a pre-load mechanismto prevent transfer of that actuating force to the container collar 30to move the canister 5 downwards along the longitudinal axis L-L of thedrug discharge device (see FIG. 5), which is coincident withlongitudinal axis H-H of the housing, to actuate the valve thereof (andhence, to fire the aerosolized drug dose) until a pre-determinedthreshold force is overcome.

Further details of the operation of the device 1 (which results from aneffective user actuation thereof) may be appreciated by making referenceto FIGS. 3 a to 4 c, and FIGS. 6 a to 6 e, in which for clarity onlyselected parts relevant to the particular stage of operation representedare labelled.

FIG. 3 a shows how the device 1 is configured in the ‘at rest’ position,in this instance also with the mouthpiece 14 covered by the mouthpiececover 16. FIG. 6 a shows in greater detail the relationship between theflexible legs 34 a, 34 b of the container collar 30 and the extensioncollar 40 in this ‘at rest’ position. The levers 20 a, 20 b are splayedapart and catch retainers 24 a, 24 b provided to an inner part of theprotruding end 23 a, 23 b of each respective lever 20 a, 20 b locateclose to ‘stop’ positions defined by notches 15 a, 15 b provided to thetop parts 10 a, 10 b of the housing. The lower ends 21 a, 21 b of eachlever 20 a, 20 b seat against the shelf 42 of the extension collar 40,but in this ‘at rest’ position no force acts on the extension collar 40.The closed coil return springs 50 a, 50 b are therefore also in their‘at rest’ state with no significant biasing return energy storedtherein. Typically, in the ‘at rest’ state the springs 50 a, 50 b willcarry a small amount of pre-load (e.g. 1-3N, such as 2N) which ispresent in order to negate any free movement between the containercollar 30 and the extension collar 40 due to tolerance variation. Eachend of the flexible support legs 34 a, 34 b is slightly spaced from itsrespective step 18 a, 18 b on the housing. This ensures the valve isclosed in the ‘at rest’ position of the device 1.

In FIG. 6 b, the device is at a first early stage of operation,corresponding to a position after removal of the mouthpiece cover 16from the mouthpiece 14, in which the levers 20 a, 20 b will have beensqueezed very slightly together. The lower ends 21 a, 21 b of each lever20 a, 20 b will have pushed slightly down on the shelf 42 of theextension collar 40 such that the extension collar 40 is moved slightlydownwards relative to the container collar 30. Importantly, as shown inFIG. 6 b, this downwards movement of the extension collar 40 brings eachouter ramp 44 a, 44 b into engagement with each outer protruding foot 36a, 36 b of the flexible support legs 34 a, 34 b. As a result of thisengagement, further downwards movement of the extension collar 30 willcause downwards force to be transferred to the flexible support legs 34a, 34 b of the container collar 30. Moreover, the downward movement ofthe extension collar 40 relative to the container collar 30 moves theinner ramps 43 a, 43 b to a position relative to the flexible supportlegs 34 a, 34 b which enables the legs 34 a, 34 b to buckle when thecommit force is achieved, as to be described shortly hereinafter.

In FIGS. 3 b and 6 c, the device is at a second early stage ofoperation, in which the levers 20 a, 20 b have been squeezed slightlymore together. The lower ends 21 a, 21 b of each lever 20 a, 20 b pushslightly down on the shelf 42 of the extension collar 40 such that theextension collar 40 is moved slightly more downwards. This furtherdownwards movement of the extension collar 40 brings each bottom end ofthe flexible support legs 34 a, 34 b into latching engagement with itsrespective step 18 a, 18 b on the housing through the driving engagementof the outer ramps 44 a, 44 b with the outer protruding feet 36 a, 36 b.As a result of this latching engagement, further downwards movement ofthe container collar 30 is impeded, with the user (patient) experiencingincreasing lever force as they continue to depress the levers 20 a, 20b.

In FIG. 4 a, the device is at a third stage of operation, in which thelevers 20 a, 20 b have been squeezed even further together. The lowerends 21 a, 21 b of each lever 20 a, 20 b push further down on the shelf42 of the extension collar 40 such that the extension collar 40 receivesdownwards force. That downwards force cannot however, be transmitted tothe container collar 30 because of the latching engagement of eachbottom end of the flexible support legs 34 a, 34 b with its respectivestep 18 a, 18 b on the housing. That latching engagement thus, impedesthe downwards movement of the container collar 30.

In FIGS. 4 b and 6 d, the device is shown at a fourth stage ofoperation, in which the levers 20 a, 20 b have been squeezed evenfurther together. The lower ends 21 a, 21 b of each lever 20 a, 20 bpush even further down on the shelf 42 of the extension collar 40 suchthat the extension collar 40 receives further downwards force. Eachouter ramp 44 a, 44 b of the extension collar 40 is brought even furtherdown on each protruding outer foot 36 a, 36 b of each flexible legsupport 34 a, 34 b thereby causing each flexible leg support 34 a, 34 bto flex inwards and to be displaced interiorly relative to the housing.Thus, FIGS. 4 b and 6 d correspond to the position at which the pre-loadthreshold force (typically about 16N) provided by the latchingengagement of the flexible legs 34 a, 34 b with their respective steps18 a, 18 b on the housing is just about to be overcome by the actuatingforce provided by the levers 20 a, 20 b to the extension collar 40. Thisposition therefore corresponds to the threshold (or ‘tipping point’) ofthe pre-load system defined by the components of the device. Applyingany further squeeze force to the levers 20 a, 20 b will result in thatthreshold being exceeded and effective user actuation of the device 1.

In FIGS. 4 c and 6 e, which corresponds to a fifth stage of operation,such further force has been applied to the levers 20 a, 20 b. Theprotruding end 21 a, 21 b (see also FIG. 3 a) of each respective lever20 a, 20 b touches off one against the other, thereby preventing anyfurther lever 20 a, 20 b travel. Most importantly, the flexible legs 34a, 34 b have flexed and become displaced from their respective steps 18a, 18 b through the action of the downward movement of the outer ramps44 a, 44 b. The extension collar 40 now moves instantaneuouslydownwards, relative to the container collar 30, as a result of itsexperience of the unrestricted actuating force resulting in the theextension collar 40 drivably engaging the stop features 37 a, 37 bprovided to container collar 30 to thereby drive the container collar 30(and hence canister 5 in permanent engagement therewith) rapidlydownwards. The valve of the canister 5 is thereby activated to releaseaerosolized drug through the passage 9 in the stem block 8 which guidesthat discharged aerosolized drug to the mouthpiece 14 for inhalation bythe patient.

The threshold force to be overcome for releasing (disengaging) the legs34 a, 34 b from the steps 18 a, 18 b should be great enough to ensureinstantaneous acceleration of the extension collar 40 when the legs 34a, 34 b are released (disengaged). This will then make the firing of thedevice (release of a metered drug dose by the valve) user-independentsince the user cannot affect the firing mechanism performance once thethreshold (commitment) force is overcome. As a result, reliable dosingfrom the device is provided for.

Following actuation, the return springs 50 a, 50 b act such as toprovide return biasing energy to move the extension collar 40 and levers20 a, 20 b back to the ‘at rest’ position as shown in FIGS. 2, 3 a and 6a. In turn, the canister 5 and container collar 30 are moved back totheir ‘at rest’ position under the action of the internal valve springof the canister valve. Further actuating operations may therefore beconducted until the canister 5 is exhausted of its drug formulationcontent. As will be appreciated by the skilled reader in the art, thereturn spring (not shown) of the valve of the valved canister may alsoprovide return biasing energy.

In a detailed aspect, during the return operation each inner protrudingfoot 35 a, 35 b of each flexible leg 34 a, 34 b interacts with eachinner ramp 43 a, 43 b of the extension collar 340, the effect of thisinteraction being to push each flexible leg 34 a, 34 b outwards to the‘at rest’ state of FIGS. 2, 3 a and 6 a, in which each flexible leg 34a, 34 b is un-flexed.

FIG. 7 shows a particular detail of the first drug dispenser device ofFIGS. 1 to 6 e. For succinctness, only those parts relevant to thisdetail are now described further.

As previously described, the container collar 30 is provided at itsunderside with two downward protrusions 38 a, 38 b. The mouthpiece cover16 is further provided with P-shaped cam interference elements 17 a, 17b joined together by bridge element 18 and joining to the mouthpiececover 16 by means of living hinge 19 about which the bridgedinterference elements 17 a, 17 b may pivot. When, as shown in FIG. 7,the mouthpiece cover 16 engages with the body 12 of the dispenser device1 to close the mouthpiece 14 (i.e. in the mouthpiece-closed position)the interference elements 17 a, 17 b adopt a position in which theylocate underneath the downward protrusions 38 a, 38 b in close proximityor abutment therewith to thereby prevent any downward movement of thecontainer collar 30. See also FIG. 3 a. Unintended movement of thecontainer collar 30 and hence, unintended actuation of the dispenserdevice 1 is hence prevented.

In a subtle point, it is noted that when the mouthpiece cover 16 is inplace such that the interference elements 17 a, 17 b prevent thedownward movement of the container collar 30 the levers 20 a, 20 b;return springs 50 a, 50 b; and extension collar 40 are not locked andare therefore free to move. The levers 20 a, 20 b may thus, still becompressed to the point at which their protruding ends 21 a, 21 b touchoff, but without any movement of the container collar 30 and actuationof the dispenser device 1.

The relative positioning of the interference elements 17 a, 17 b and thecollar protrusions 38 a, 38 b in the various stages of operation of thedevice 1 is shown in FIGS. 3 a to 4 c. FIG. 3 a shows the spatialrelationship between these parts when the mouthpiece cover 16 is in themouthpiece-closed position, whilst FIGS. 3 b and 4 a-4 c show thecorresponding spatial relationship with the cover 16 removed and thelevers being depressed inwardly to fire the device 1.

The mouthpiece cover 16 may take one of the particular forms describedin PCT Patent Application No. WO-A-2007/028992, which claims priorityfrom UK patent application No. 0 518 355 filed 8 Sep. 2005, the entirecontent of which applications, and any subsequent US (PCT) patentapplication, are incorporated herein by reference.

FIGS. 8 to 11 illustrate aspects of the air flow into and through thehousing of the drug dispenser device of FIG. 1 during use thereof. Itwill be observed that the levers 20 a, 20 b in these Figures show aminor ergonomic restyling compared to the previous Figures, whichrestyling does not alter their technical function. For succinctness,only those parts of the drug dispenser relevant to these aspects are nowdescribed.

FIG. 8 shows the drug dispenser device 1 of FIG. 1 in a ‘ready to use’position with the mouthpiece cover 16 removed from the mouthpiece 14. Itwill be noted that in this position, the mouthpiece cover 16 is pivotedto a position underneath the lower housing part 12. The opposing levers20 a, 20 b, which protrude from apertures 11 a, 11 b provided to thefront 10 a and rear 10 b upper housing parts, are in their restposition. It will also be noted that in this position, the opposinglevers 20 a, 20 b act to block off the apertures 11 a, 11 b such as toprevent ingress of dirt particles or other debris into the body of thedevice 1.

FIG. 9 shows the drug dispenser device 1 of FIG. 1 in the ‘in use’position, in which the opposing levers 20 a, 20 b have been movedtowards each other, typically in response to a patient finger and thumbsqueezing action. In this position, the opposing levers 20 a, 20 b nolonger act to block off the apertures 11 a, 11 b such that air 60 a, 60b may flow through the opened up apertures 11 a, 11 b into the upperhousing part 10 a, 10 b in response to patient inhalation 61 through themouthpiece 14.

The air flow ‘in use’ through the device 1 is now described in moredetail with reference to FIGS. 10 and 11.

FIG. 10 shows one half of the device 1 of FIG. 1 in the ‘in use’position, in which the mouthpiece 14 is revealed, and in which lever 20b has been pushed inwards to open up aperture 11 b. External air 60 bmay thus, now be drawn into the body of the device housing through thisaperture 11 b (and also similarly through aperture 11 a on the otherside) in response to patient inhalation through the mouthpiece 14. Inother words, the patient coordinates their inhalation at the mouthpiece14 to depression of the levers 20 a, 20 b so that the resulting airflowthrough the housing 10 a, 10 b, which enters via the opened apertures 11a, 11 b and exits through the mouthpiece 14, is coincident with therelease of the drug from the canister 5 caused through actuation of thelevers 20 a, 20 b. The airflow thus entrains the drug into therespiratory tract of the patient.

FIG. 11 illustrates in more detail, the air flow 60 a, 62 through thebody of the device 1 during use thereof (i.e. again with the device 1 inthe ‘in use’ position of FIGS. 9 and 10).

Referring to FIG. 11 in more detail, the device 1 may be seen tocomprise a discharge assembly in the form of a stem block assembly 3which is integrally formed with the lower body part 12 and provides forthe delivery of an aerosol spray of a drug on actuation of the inhaler.Mouthpiece 14 is a separately formed part which is fitted to the lowerbody part 12 and in use is gripped in the lips of the user to facilitateoral inhalation. Received within the an enclosed chamber defined by thehousing parts 10 a, 10 b, 12 there is provided aerosol canister 5 whichcontains drug to be delivered on actuation of the inhaler and is fittedin the main body and fluidly connected to the stem block assembly 3.

The mouthpiece 14 comprises an external section 15 which is configuredto be gripped in the lips of a subject and defines a substantiallycylindrical, open forward end through which an aerosol spray of a drugis in use delivered on actuation of the inhaler, an essentially‘bucket-shaped’ open chamber form internal section 17 which has a closedrear section (other than air holes 66 and spray orifice 72 describedhereinafter), and a discharge outlet in the form of a nozzle outlet 70which is coupled to a rear end of the internal section 17, such as toprovide for the delivery of an aerosol spray 64 into and through theinternal section 17.

In response to patient inhalation, air 60 a is drawn down the rear part10 b of the body of the device 1 past around the stem block assembly 3and towards the rear of the internal section 17 of the mouthpiece 14,which is provided with a duality of slot-like air holes 66 at the rear(i.e. base of the ‘bucket’) thereof arranged about spray orifice 72. Theair holes 66 may be equi-spaced from the spray orifice 72. As may beseen, when the air 60 a is drawn through these dual air holes 66 aduality of air flows 62 is defined within the mouthpiece 14. Thisprovides for a partly annular air flow at the inner peripheral surfaceof the mouthpiece 14, which partly sheaths the aerosol spray 64 asdelivered from the spray orifice 72 of the nozzle outlet 70, therebypartly entraining the aerosol spray 64 and reducing deposition at theinternal surface of the mouthpiece 14.

In this embodiment the rear of the internal section 17 has a generallyflat shape, which forms the base of the ‘bucket’. The edges of the basecurve outwards such that the internal section 17 has an increasinginternal dimension in a direction away from the stem block assembly 3.

The nozzle outlet 70 includes the spray orifice 72 which provides forthe delivery of an aerosol spray through the internal section 17 of themouthpiece 14 and a delivery channel 74 which fluidly connects thedelivery passage 9 of the stem block assembly 3 to the spray orifice 72.

In this embodiment the delivery channel 74 is a tapering channel whichnarrows towards the spray orifice 74. In this embodiment the deliverychannel 74 has straight wall sections.

In this embodiment, the stem block assembly 3 comprises the stem block 8for receiving the valve stem 7 of the canister 5, and the nozzle outlet70 of the mouthpiece 14 which is fluidly connected to the stem block 8,such as to provide for the delivery of an aerosol spray through themouthpiece 14. The stem block 8 may be integrally formed with the lowerbody part 12.

The stem block 8 includes a tubular bore 76 for receiving the valve stem7 of the canister 5, which in this embodiment is co-axial with thelongitudinal axis H-H of the housing (FIG. 3 a), which housing axis H-Hin this embodiment is coincident with the longitudinal axis L-L of thedrug delivery device when mounted in the drug dispenser device 1. Thetubular bore 76 is open at one, the upper, end thereof and includes anupper section 77 which has an internal dimension which is substantiallythe same as the outer dimension of the valve stem 7 of the canister 5and a lower section 78 which has a smaller dimension, which sections 77,78 together define an annular seat for the distal end of the valve stem7.

In this embodiment, the stem block 8 includes a lateral cavity 80 whichslidingly receives the nozzle outlet 70 of the mouthpiece 14 and isfluidly connected to the tubular bore 76 thereof. The nozzle outlet 70is configured to be a tight friction fit in the lateral cavity 80 in thestem block 8. Desirably, the tight friction fit provides a gas-tightseal. In other embodiments, other types of sealing method, alsopreferably arranged to provide a gas-tight seal, may be employed.

With this configuration of the stem block assembly 3, the nozzle outlet70 (or mouthpiece 14) and the nozzle block 8 (or lower housing part 12)can be formed of different materials and to different specificationswhich are specifically suited to their purposes.

FIG. 12 shows a variation 101 of the drug dispenser device of FIGS. 1 to11, with like features being identified with like reference numerals.The device 101 of FIG. 12 is identical to the embodiment of FIGS. 1 to11 in all aspects other than that the dual horizontal slot-like airholes 66 visible in FIG. 11 are replaced by an arrangement of fourcircular air holes 166 (only three visible in FIG. 12) about the sprayorifice 172 at the rear (i.e. base of the ‘bucket’) of the internalsection 117 of the mouthpiece 114. It may be seen that the four airholes 166 are arranged in a generally circular arrangement about thespray orifice 172, in this embodiment being at 90° angular displacementrelative to each other. The spray orifice 172 may be centrally locatedin the circular arrangement of the air holes 166. As may be seen in FIG.11, when external air 160 a is drawn through these plural spaced airholes 166 a plurality of air flows 162 is defined within the mouthpiece114. This provides for an essentially annular air flow at the innerperipheral surface of the mouthpiece 114, which essentially sheaths theaerosol spray 164 as delivered from the spray orifice 172 of the nozzleoutlet 170, thereby entraining the aerosol spray and reducing depositionat the internal surface of the mouthpiece 114.

FIGS. 25 a to 25 n show other mouthpiece forms 514 a to 514 n, which maybe employed in the drug dispenser device of FIGS. 1 and 11 as analternative to the mouthpieces 14, 114 thereof. These alternativemouthpiece forms 514 a to 514 n differ only in the size, shape andnumber of respective air holes 566 a to 566 n provided to the rear ofthe internal section 517 a to 517 n of these alternative mouthpieceforms 514 a to 514 n, which air holes 566 a to 566 n are as before,arranged about a spray orifice 572 a to 572 n.

Thus, FIGS. 25 a to 25 d and 25 i show different arrangements of fourcircular air holes 566 a to 566 d and 566 i; FIGS. 25 e and 25 f showdifferent arrangements of three slot-like air holes 566 e, 566 f; FIGS.25 g and 25 h show different arrangements of six slot-like air holes 566g, 566 h; FIG. 25 j shows an arrangement of many circular air holes 566j; FIG. 25 k shows an arrangement of six curved slot air holes 566 karranged in two concentric rings; FIGS. 25 l to 25 n show differentarrangements of three curved slot air holes 566 l to 566 n arranged in aring pattern.

Other air flow pathways through the drug dispenser device are possible,for instance such as those described in U.S. Provisional Application No.60/823,146 filed on 22 Aug. 2006 and the International (PCT) PatentApplication WO-A-2008/023014 which claims priority therefrom anddesignates the United States of America.

The upper front part 10 a of the drug dispenser device 1, 101 of FIGS. 1and 12 is arranged for receipt and housing of an actuation counter.FIGS. 13 to 19 b provide details of the workings of a suitable actuationcounter. FIGS. 20 to 22 show more details of the interaction of theactuation counter with the actuating mechanism of the drug dispenserdevice 1, 101.

Referring now to FIG. 13, this shows an actuation counter 201 for usewith the drug dispenser device 1, 101 herein. FIGS. 14 a and 14 brespectively show underside and top views of the actuation counter 201.

The actuation counter 201 is comprised within upper front part 10 a ofthe drug dispenser device 1 (or 101) provided with first 212 and second214 spindle mountings, each capable of defining an axis of rotation anda circumferential wall 218 defining a bezel form retainer 219. A viewingwindow 216 is provided to the housing to enable the viewing of thecount. As will be understood by a comparison of FIG. 1 with FIG. 14 b,the oval-shaped front face 101 of the upper front part 10 a is coveredwith a correspondingly shaped label 103 to cover the apertures in thefront face 101 shown in FIG. 14 b, but not the viewing window 216. Inother words, the label has an aperture 105 which registers with theviewing window 216. In an alternative embodiment, the label 103 mayitself have a transparent portion in place of the aperture 105 to enableobservation of the viewing window 216.

Now describing the workings of the actuation counter in more detail:First, disc-shaped count wheel 220 has ‘units’ (Le. numerals) countindicia 222 provided at spaced intervals on a top face thereof. Thefirst count wheel 220 is provided with a central aperture 226 and acircular cavity 223 that is arranged for disposed receipt of ratchetwheel 250. Ratchet drive receipt teeth 224 are arranged about the innercircumferential wall 225 of the cavity for ratcheted drive interactionwith the ratchet wheel 250. The ratchet wheel 250 itself, is sized andshaped for receipt by the circular cavity 223 of the first count wheeland is provided with two oppositely-located drive tongues 252 a, 252 bfor ratcheted drive interaction with the ratchet drive receipt teeth224. The ratchet wheel 250 is also provided with a drive-receivingprotrusion 254 arranged in use, for drivable rotation of the ratchetwheel 250. As will be described in more detail hereinafter withreference to FIGS. 20 to 22, the drive-receiving protrusion 254 receivesdrive in response to drive interaction with downward drive slot 82provided to front plate 80 in which the drive-receiving protrusion 254is located. The front plate 80 is permanently fixed to the containercollar 30 so as to move in tandem therewith. In this embodiment, thefront plate 80 is permanently fixed to the container collar 30 byultrasonic welding.

Noting that the front plate 80 moves on a linear path (along axis L-L)on actuation of the drug dispenser device 1, 101 and that the ratchetwheel 250 rotates, the drive slot 82 allows for the transverse componentof motion of the drive-receiving protrusion 254 therein as the ratchetwheel 250 rotates upon the drive-receiving protrusion 254 being drivenby the drive slot 82.

Second, ring form count wheel 230 also has ‘tens of units’ (i.e.decimals) count indicia 232 provided at spaced intervals on a top face237 thereof and a set of teeth 234 provided in annular arrangement tothe underside thereof. It may be noted that at stop position 238, acouple of the teeth 234 have been removed and further that the outercircumferential edge of top face 237 is formed with a series of equallyspaced notches or indentations 236. The reasons for these features willbecome clear from the later description. The second count wheel 230 isalso provided with a protruding shutter 280, the function of which willalso be described later.

Kick wheel 240 has kick teeth 244 provided in annular arrangement aroundthe circumference thereof.

As may be best seen at FIG. 14 a, when assembled, second count wheel 230is received for rotation within the bezel form retainer 219 of thehousing; and first count wheel 220 is received within the inner ringvoid 235 defined by ring-shaped second count wheel 230 and its centralaperture 226 by first spindle 212 such that clearance exists between thefirst 220 and second 230 count wheels. Thus, the first 220 and second230 count wheels are in concentric relationship, but the level of thesecond count wheel 230 is slightly raised relative to that of the firstcount wheel 220 to enable shutter 280 to protrude over and above thefirst count wheel 220. Ratchet wheel 250 is received within the circularcavity 223 of the first count wheel 220 such that drive tongues 252 a,252 b engage with the ratchet drive receipt teeth 224. Both wheels 220,230 and the ratchet wheel 250 are rotatable about a common first axis ofrotation F-F defined in combination by the axis of first spindle 212 andthe circular shape of the bezel retainer 219. The drive-receivingprotrusion 254 is offset from the first axis F-F, as is the drive slot82. Moreover, the protrusion 254 and drive slot 82 are both offset tothe longitudinal axis L-L.

Kick wheel 240 is received by second spindle 214 for rotation about asecond axis of rotation S-S defined by the second spindle 214 andtherefore offset from the first axis of rotation F-F. It will beappreciated that the second axis of rotation S-S is spaced from thefirst axis of rotation F-F to be outside ‘the path of ‘rotation definedby the outwardly-facing teeth 234 of the second count wheel 230.Moreover, the first and second axes F-F, S-S are parallel, orsubstantially parallel, to each other.

The set of kick teeth 244 of the kick wheel 240 are in meshedrelationship with the set of teeth 234 of the second count wheel 230such that rotary motion of the kick wheel 240 results in rotary motionof the second count wheel 230. In turn, ratchet drive tongues 252 a, 252b of ratchet wheel 250 mesh with the ratchet drive receipt teeth 224 ofthe first count wheel 220 for drivable rotation of the first count wheel220.

As will be described in more detail hereinafter, when the actuationcounter 201 is disposed in the drug dispenser 1, 101 the ratchet wheel250 is in turn drivably rotatable about the first axis F-F by thedrive-receiving interaction of protrusion 254 with downward drive slot82 provided to front plate 80. The front plate 80 fixes to the containercollar 30, which is itself drivable downwards in response to effectiveuser actuation of the drug dispenser device 1, 101.

First count wheel 220 may also be seen to be provided at its peripherywith a pair of fixed index teeth 228 a, 228 b (as may be best seen inFIG. 16 a) arranged for intermittent meshing with the kick teeth 244 ofthe kick wheel 240 such that rotary motion of the kick wheel 240 resultsfrom rotary motion of the first count wheel 220 only when saidintermittent meshing occurs.

In a subtle aspect, it may be seen that the profile of all teeth 234,228 a, 228 b, 244 has a flanged form, which is selected to optimise thevarious toothed engagements necessary for effective gearing andinter-operability of the parts of the counter.

In a further subtle aspect, the counter 201 is arranged to count downfrom ‘120’ to a ‘shuttered position’. The second count wheel 230 isthus, arranged to define fourteen equal pitches allied to twenty-six(calculated as (2×14)−2) teeth 234 plus two missing teeth at stopposition 238. The number of pitches is defined as x+2, wherein x is thehighest numeral on the second count (i.e. decimals) wheel, which in turncorresponds to a highest count of 10 times× (i.e. 10×12=120, in thisembodiment). The ‘+2’ part of the sum determining the number of pitchesrelates to one coloured portion 282 and one shutter portion 280, as aredescribed in more detail later.

Overall, it may be noted that the actuation counter 201 has a relativelycompact form to assist its receipt within the upper front housing part10 a of the drug dispenser device 1, 101. In particular, the counter 201extends upwards in the direction of the axes F-F, S-S to only a minorextent.

Operation of the actuation counter 201 is now described with additionalreference to FIGS. 15 a to 17 b, in which only the most relevantfeatures to the described operation are labelled. The actuation counter201 is arranged to count down and thus, to illustrate a count operation,FIGS. 15 a, 17 a and 17 a show the actuation counter 201 at a ‘count120’ position and FIGS. 15 b, 16 b and 17 b show the actuation counter201 at a ‘count 119’ position (i.e. just after counting down from 120).

It will be appreciated that the ‘count’ of the dose counter 201 referredto herein is the count number collectively presented by the count wheels220, 230 in the window 216.

To initiate a general count operation, ratchet wheel 250 is rotated inresponse to effective user actuation of the drug dispenser device 1, 101by squeezing the levers 20 a, 20 b together as described with referenceto FIGS. 1 to 6 e above. This results in the drive slot 82 driving theratchet wheel protrusion 254 to rotate the ratchet wheel 250 in a firstrotary sense (clockwise in FIGS. 13 and 14 a). This, in turn, results inrotation of the first count wheel 220 in the first rotary sense by themeshed interaction of drive tongues 252 a, 252 b with ratchet drivereceipt teeth 224. The ratchet wheel 250 and first count wheel 220 areconfigured and arranged such that when indexed first count wheel 220rotates by 36° such that a single indicium 222 thereon is advanced (i.e.the ‘units’ count moves down one unit).

Where the pre-count operation visible count is x0 (e.g. 120 with ‘x=12’,as shown at FIGS. 15 a, 16 a and 17 a), the counting action resultingfrom the use operation is subtly different. Once again, ratchet wheel250 is rotated in response to effective user actuation of the drugdispenser device 1, 101 causing rotation of the first count wheel 220 by36° such that the ‘unit’ indicium 222 moves on from ‘0’ to ‘9’ (as shownat FIGS. 15 b and 16 b). This rotation of the first count wheel 220however, also brings the pair of index teeth 228 a, 228 b into meshedrelationship with the kick teeth 244 of kick wheel 240 such that thekick wheel 240 rotates and in turn, causes the second count wheel 230 torotate through meshing of their respective teeth 234, 244. The wheels220, 230, 240 are configured and arranged such that the resultantrotation of the second count wheel 230 is by 360/14° (that is to say by360/n° wherein n is the number of number spacings, where in this casen=14 because there are twelve decimals indicia 232; one shutter portion280 and one coloured portion 282) such that a single indicium 232thereon is advanced (i.e. the ‘tens’ count moves down exactly one unit).In this instance, the decimal indicium 232 moves down from ‘12’ to ‘11’,as shown in FIGS. 15 a and 15 b.

Where the previous visible count was 10 (i.e. x=1), the counting actionresulting from the use operation is again subtly different in that thekick wheel 240 action, as described above, results in the coloured (e.g.red) portion 282 of the second count wheel 230 being advanced into placein the window 216 such that the next display is ‘red 9’ (i.e. colouredportion 282; and numerals indicia 222 is number 9).

As shown at FIGS. 18 a and 19 a, where the previous visible count was‘red 0’ (i.e. x=0), the counting action resulting from the use operationis still again subtly different in that the kick wheel 240 action, asdescribed above, results in the shutter portion 280 of the second countwheel 230 being advanced into place in the window 216 such that the nextdisplay is fully shuttered off (i.e. no indicia 222, 232 visible at all,as shown at FIGS. 18 b and 19 b). Additionally, the stop position 238 inthe set of second count wheel teeth 234 is brought into opposed relationwith the kick teeth 244 whereby the kick teeth 244 and the teeth 234 nolonger mesh. Thus, if the first count wheel 220 continues to rotate,e.g. in response to continued user operation of the drug dispenserdevice 1, 101 into which the actuation counter 201 is incorporated,notwithstanding that all drug doses in the prescribed dosing regime havebeen dispensed (although surplus doses may remain in the canister 5 forpatient administration in accordance with regulatory requirements, asunderstood by the skilled person in the art), the index teeth 228 a, 228b of the first count wheel 220 will still intermittently mesh with thekick teeth 244 to cause the kick wheel 240 to rotate. However, thisrotation of the kick wheel 240 will not be transmitted to the secondcount wheel 230, due to the missing teeth of stop position 238, and theshutter 280 remains in the shuttering position in the window 216 so thatthe underlying ‘units’ indicium 222 remains unseen.

In this embodiment, the second count wheel 230 is integrally formed withthe shutter portion 280.

To further illustrate the countdown display of the counter 201, thereader's attention is drawn to Table 1 below. Table 1 shows thesequential countdown for each of the units (first) and decimals (second)count wheels 220, 230 upon succeeding use operations or actuations ofthe counter 201, and also indicates which of these two count wheels 220,230 indexes to bring the counter 201 to its new counter display. Asshown in Table 1, the first (units) count wheel 220 indexes on eachcounter 10 actuation, whereas the second (decimals) count wheel 230 onlyindexes (through the kick wheel 240 supra) each time the units indicium222 of the first (units) count wheel 220 in the window 216 decrementsfrom ‘0’ to ‘9’. At the end of the countdown, when the display isshuttered, the first count wheel 220 is still free to rotate, underneaththe shutter 280 so as not to be visible, and no further indexing of thesecond count wheel 230 occurs due to the stop position 238 providing fordisengagement of the teeth 234, 244 of the second count wheel 230 andthe kick wheel 240.

TABLE 1 Sequential Indexing of Indexing of Counter Decimals Units WheelUnits Wheel Decimal Wheel Display in Wheel Count Count in to this tothis Window in Window Window Count? Count? 120  12 0 — — 119  11 9 YesYes 118-110 11 8 to 0 Yes No 109  10 9 Yes Yes 108-100 10 8 to 0 Yes No99 9 9 Yes Yes 98-90 9 8 to 0 Yes No 89 8 9 Yes Yes 88-80 8 8 to 0 YesNo 79 7 9 Yes Yes 78-70 7 8 to 0 Yes No 69 6 9 Yes Yes 68-60 6 8 to 0Yes No 59 5 9 Yes Yes 58-50 5 8 to 0 Yes No 49 4 9 Yes Yes 48-40 4 8 to0 Yes No 39 3 9 Yes Yes 38-30 3 8 to 0 Yes No 29 2 9 Yes Yes 28-20 2 8to 0 Yes No 19 1 9 Yes Yes 18-10 1 8 to 0 Yes No  9 ‘Red’ 9 Yes Yes 8-0‘Red’ 8 to 0 Yes No Shuttered Shuttered Shuttered Yes Yes

After effective user actuation of the drug dispenser device 1, 101 andregistration of the count, the levers 20 a, 20 b are released to returnto their outward rest position and to allow the container collar 30 toreturn to its rest position. This results in the ratchet wheel 250reversing, to reset it in its starting position for the next countingevent, through interaction of the drive slot 82 with the drive-receivingprotrusion 254.

Thus, the ratchet wheel 250 is adapted to not only rotate in the cavity223 of the first count wheel 220 in the first rotary sense (clockwise asviewed in FIGS. 13 and 14 a), but also to rotate in an opposite, secondrotary sense (anti-clockwise as viewed in FIGS. 13 and 14 a) in thefirst count wheel cavity 223.

However, while rotation of the ratchet wheel 250 in the first rotarysense drivably rotates the first count wheel 220 in the first rotarysense for indexing of the units count 222 in the window 216, rotation ofthe ratchet wheel 250 in the opposite, second rotary sense is relativeto the first count wheel 220; i.e. the first count wheel 220 remainsstationary so that the units indicia 222 in the window 216 remainsunchanged. That is to say, frictional engagement between the respectivewheels 220, 250 does not result in reverse rotation of the first countwheel 220, except for tolerance adjustments as discussed below.

To this end, the first count wheel 220 is provided with a pair ofdiametrically opposed resilient tongues or pawls 227 which co-operatewith a serrated circumferential surface 211 of the first spindle 212 a.The serrated surface 211 comprises plural ratchet teeth 215 with whichthe free ends 227 a of the pawls 227 engage. As the skilled person willunderstand, as the first count wheel 220 is driven by the ratchet wheel250 to rotate in the first sense, the free ends 227 a of the pawls 227ride over the respective ratchet tooth 215 presently engaged with anddrop onto the next adjacent ratchet tooth 215 in the first sense, therebeing a step between adjacent teeth 215. This then indexes the firstcount wheel 220 in its new position, at which the next units indicia 222in the count sequence registers with the window 216. However, the stepbetween the adjacent ratchet teeth 215 prevents the first count wheel220 rotating back in the opposite, second sense as the ratchet wheel 250so rotates as the pawl free ends 227 a cannot pass thereover.

As will also be appreciated by the skilled person, the ratchet teeth 215provide tolerances in the indexing rotation of the first count wheel 220by the ratchet wheel 250. In other words, the first count wheel 220 canbe slightly over-rotated in the first sense, but as the ratchet wheel250 rotates back in the opposite, second sense it carries the firstcount wheel 220 in the same sense, through frictional forces, until thepawl free ends 227 a engage the step between the ratchet teeth 215 whichthen prevents further reverse rotation of the first count wheel 220 andindexes the units indicia 222 in the window 216.

As shown in FIGS. 13 and 14 b, for example, the upper front part 210 ofthe drug dispenser device 1, 201 further provides a resilient pawl 217.The pawl 217 has a free end 217 a which engages the indentations 236 inthe outer circumferential surface of the top face 237 of the secondcount wheel 230, as shown in FIGS. 15 a and 15 b, for instance. There isone indentation 236 for each count or index position of the second countwheel 230, so the free end 217 a of the pawl 217 and the indentations236 provide an indexing function which provides for accurate alignmentof the decimals indicia 234 in the window 216 and inhibits or preventsreverse rotation of the second count wheel 230.

The indentations 236 in this embodiment have a symmetrical shape, moreparticularly a generally U-shape. However, other shapes could be used.Moreover, asymmetric shapes could also be used. For instance, it may beuseful for the flanks of the indentations 236 to present differentangles, for example for the trailing (rear) flanks of the indentations236 (relative to the direction of rotation of the second count wheel230, e.g. anti-clockwise in FIGS. 15 a and 15 b) to form a greater anglewith a central radial line through the indentations 236 than the leading(forward) flanks. This means there is less resistance to the pawl 217releasing from the indentations 236 as the second count wheel 230 isdriven by the kick wheel 240.

It will be appreciated that the above usage of the actuation counter hasbeen described in terms of a counter assembly 201 arranged to countdownwards (i.e. to count on from ‘n+1’ to ‘n’ on indexing), but that thecounter assembly may be straightforwardly modified to count upwards(i.e. instead to count on from ‘n’ to ‘n+1’ on indexing).

The components of the actuation counter 201 and any assemblies andsub-assemblies described above may be made from any suitable materialssuch as plastic polymer materials (e.g. acetal or ABS or styrenepolymers).

In a modification of the counter 201 (not shown), the frictionresistance between the kick wheel 240 and its spindle mounting 214 maybe increased to provide a dragging or braking effect which retards thespeed of rotation of the kick wheel 240 when driven by the first countwheel 220. One possible way to achieve this is through the provision ofaxially-oriented splines about the outer periphery of the spindlemounting 214. This may prevent or inhibit any tendency for the secondcount wheel 230 to be misaligned or over-indexed by a fast moving kickwheel 240.

The interrelationship between the actuation counter 201 and the drugdispenser device 1 is now described in more detail with reference toFIGS. 20 to 22. For clarity and succinctness, only relevant parts ofFIGS. 20 to 22 are labelled.

FIG. 20 shows the drug dispenser device 1 with upper front cover part 10a and actuation counter 201 removed. The device 1 is in the ‘at rest’position with the levers 20 a, 20 b not depressed.

FIG. 21 shows the drug dispenser device 1 with the upper front coverpart 10 a and actuation counter 201 disposed therein shown detached fromthe remainder of the device 1. The drug dispenser device 1 is again inthe ‘at rest’ position with the levers 20 a, 20 b not depressed. FIG. 22shows further details of the actuation counter 201 disposed in the upperfront cover part 10 a of the drug dispenser device 1.

Arrow A of FIG. 21 indicates the direction of movement of the containercollar 30 and front plate 80 attached thereto resulting from effectiveuser actuation of the drug dispenser device. Arrow B of FIG. 21indicates the resulting interaction between the downward drive slot 82of the front plate 80 and the drive-receiving protrusion 254 of theratchet wheel 250 of the actuation counter 201.

Detailed aspects of the drug dispenser device 1 and actuation counter201 of FIGS. 20 to 22 correspond to those already described by referenceto FIGS. 1 to 12 and FIGS. 13 to 19 b respectively, and for succinctnessthese are not described further.

Registration of a count is now described. In use, following effectiveuser actuation of the drug dispenser device 1 by squeezing the levers 20a, 20 b together, as described hereinabove with reference to FIGS. 1 to6 e, the container collar 30 and front plate 80 move downwards intandem. The downward drive slot 82 on the front plate 80 drivablyengages the drive-receiving protrusion 254 to drive on the ratchet wheel250 of the actuation counter thereby resulting in registration of acount. As described previously, effective user actuation which resultsin the downward movement of the container collar 30 (and actuation ofdrug release from the canister 5) occurs only once a pre-load threshold(‘tipping’) force has been overcome (by that effective user actuation).Thus, it will also be appreciated that a count is only registered by theactuation counter 201 in response to such an effective user actuation.The registered count thus, fully ties in with the number of occurrencesof drug release.

Where not stated, the components of the drug dispenser devices hereinmay be made from conventional engineering materials, especiallyconventional engineering plastics materials, more especially those whichallow moulding of the component.

The illustrated drug dispenser devices in accordance with the presentinvention have inter alia the following advantages:

-   -   a “reduced force to fire” through use of the side levers;    -   a lock-out to prevent inadvertent firing of the device;    -   a patient independent firing characteristic through provision of        the commitment feature;    -   an inhalation airflow path which sheaths the drug plume in the        mouthpiece thereby reducing deposition of drug on the        mouthpiece;    -   a closed-off internal mouthpiece geometry which makes it easier        to keep the mouthpiece clean; and    -   a multi-part stem block which enables complex moulding        geometries to be used for the spray channel.

Each of the above-described embodiments may be modified to incorporateone or more features disclosed in the U.S. Provisional and/orInternational Applications incorporated herein by reference in thesecond to fourth paragraphs hereof.

It will be appreciated that the mouthpiece 14 in the exemplaryembodiments could be configured instead as a nasal nozzle for insertionin a nostril of a human being, so that the drug formulation isdeliverable to the nasal cavity of the human being.

The drug dispenser device herein is suitable for dispensing of a drugformulation to a patient. The drug formulation may take any suitableform and include other suitable ingredients such as diluents, solvents,carriers and propellants.

Administration of drug may be indicated for the treatment of mild,moderate or severe acute or chronic symptoms or for prophylactictreatment. It will be appreciated that the precise dose administeredwill depend on the age and condition of the patient, the particular drugused and the frequency of administration and will ultimately be at thediscretion of the attendant physician. Embodiments are envisaged inwhich combinations of drugs are employed.

Appropriate drugs may thus be selected from, for example, analgesics,e.g., codeine, dihydromorphine, ergotamine, fentanyl or morphine;anginal preparations, e.g., diltiazem; antiallergics, e.g., cromoglycate(e.g. as the sodium salt), ketotifen or nedocromil (e.g. as the sodiumsalt); antiinfectives e.g., cephalosporins, penicillins, streptomycin,sulphonamides, tetracyclines and pentamidine; antihistamines, e.g.,methapyrilene; anti-inflammatories, e.g., beclomethasone (e.g. as thedipropionate ester), fluticasone (e.g. as the propionate ester),flunisolide, budesonide, rofleponide, mometasone e.g. as the furoateester), ciclesonide, triamcinolone (e.g. as the acetonide) or6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl)ester; antitussives, e.g.,noscapine; bronchodilators, e.g., albuterol (e.g. as free base orsulphate), salmeterol (e.g. as xinafoate), ephedrine, adrenaline,fenoterol (e.g. as hydrobromide), salmefamol, carbuterol, mabuterol,etanterol, naminterol, clenbuterol, flerbuterol, bambuterol,indacaterol, formoterol (e.g. as fumarate), isoprenaline,metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol (e.g. asacetate), reproterol (e.g. as hydrochloride), rimiterol, terbutaline(e.g. as sulphate), isoetharine, tulobuterol or4-hydroxy-7-[2-[[2-[[3-(2-phenylethoxy)propyl]sulfonyl]ethyl]amino]ethyl-2(3H)-benzothiazolone;adenosine 2a agonists, e.g.2R,3R,4S,5R)-2-(6-Amino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol(e.g. as maleate); α₄ integrin inhibitors e.g.(2S)-3-[4-({[4-(aminocarbonyl)-1-piperidinyl]carbonyl}oxy)phenyl)-2-[((2S)-4-methyl-2-{[2-(2-methylphenoxy)acetyl]amino}pentanoyl)amino]propanoicacid (e.g. as free acid or potassium salt), diuretics, e.g., amiloride;anticholinergics, e.g., ipratropium (e.g. as bromide), tiotropium,atropine or oxitropium; hormones, e.g., cortisone, hydrocortisone orprednisolone; xanthines, e.g., aminophylline, choline theophyllinate,lysine theophyllinate or theophylline; therapeutic proteins andpeptides, e.g., insulin or glucagon; vaccines, diagnostics, and genetherapies. It will be clear to a person skilled in the art that, whereappropriate, the drugs may be used in the form of salts, (e.g., asalkali metal or amine salts or as acid addition salts) or as esters(e.g., lower alkyl esters) or as solvates (e.g., hydrates) to optimisethe activity and/or stability of the drug.

The drug formulation may in embodiments, be a mono-therapy (i.e. singleactive drug containing) product or it may be a combination therapy (i.e.plural active drugs containing) product.

Suitable drugs or drug components of a combination therapy product aretypically selected from the group consisting of anti-inflammatory agents(for example a corticosteroid or an NSAID), anticholinergic agents (forexample, an M₁, M₂, M₁/M₂ or M₃ receptor antagonist), otherβ₂-adrenoreceptor agonists, antiinfective agents (e.g. an antibiotic oran antiviral), and antihistamines. All suitable combinations areenvisaged.

Suitable anti-inflammatory agents include corticosteroids and NSAIDs.Suitable corticosteroids which may be used in combination with thecompounds of the invention are those oral and inhaled corticosteroidsand their pro-drugs which have anti-inflammatory activity. Examplesinclude methyl prednisolone, prednisolone, dexamethasone, fluticasonepropionate,6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3S-yl) ester, beclomethasone esters (e.g.the 17-propionate ester or the 17,21-dipropionate ester), budesonide,flunisolide, mometasone esters (e.g. the furoate ester), triamcinoloneacetonide, rofleponide, ciclesonide, butixocort propionate, RPR-106541,and ST-126. Preferred corticosteroids include fluticasone propionate,6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tetramethycyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carbothioicacid S-cyanomethyl ester,6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-(1-methycyclopropylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester and 9α,21 dichloro-11β,17α methyl-1,4pregnadiene 3,20 dione-17-[2′]furoate(mometasone furoate).

Further corticosteroids are described in WO02/088167, WO02/100879,WO02/12265, WO02/12266, WO05/005451, WO05/005452, WO06/072599 andWO06/072600.

Non-steroidal compounds having glucocorticoid agonism that may possessselectivity for transrepression over transactivation and that may beuseful are disclosed WO03/082827, WO98/54159, WO04/005229, WO04/009017,WO04/018429, WO03/104195, WO03/082787, WO03/082280, WO03/059899,WO03/101932, WO02/02565, WO01/16128, WO00/66590, WO03/086294,WO04/026248, WO03/061651, WO03/08277, WO06/000401, WO06/000398 andWO06/015870.

Suitable NSAIDs include sodium cromoglycate, nedocromil sodium,phosphodiesterase (PDE) inhibitors (e.g. theophylline, PDE4 inhibitorsor mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors ofleukotriene synthesis, iNOS inhibitors, tryptase and elastaseinhibitors, beta-2 integrin antagonists and adenosine receptor agonistsor antagonists (e.g. adenosine 2a agonists), cytokine antagonists (e.g.chemokine antagonists), inhibitors of cytokine synthesis or5-lipoxygenase inhibitors. Examples of iNOS inhibitors include thosedisclosed in WO93/13055, WO98/30537, WO02/50021, WO95/34534 andWO99/62875. Examples of CCR3 inhibitors include those disclosed inWO02/26722.

Suitable bronchodilators are β₂-adrenoreceptor agonists, includingsalmeterol (which may be a racemate or a single enantiomer, such as theR-enantiomer), for instance salmeterol xinafoate, salbutamol (which maybe a racemate or a single enantiomer, such as the R-enantiomer), forinstance salbutamol sulphate or as the free base, formoterol (which maybe a racemate or a single diastereomer, such as the R,R-diastereomer),for instance formoterol fumarate or terbutaline and salts thereof. Othersuitable β₂-adrenoreceptor agonists are3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide,3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymethyl)phenyl]ethyl}-amino)heptyl]oxy}propyl)benzenesulfonamide,4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl)-2-(hydroxymethyl)phenol,4-{(1R)-2-[(6-{4-[3-(cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl)-2-(hydroxymethyl)phenol,N-[2-hydroxyl-5-[(1R)-1-hydroxy-2-[[2-4-[[(2R)-2-hydroxy-2-phenylethyl]amino]phenyl]ethyl]amino]ethyl]phenyl]formamide,andN-2{2-[4-(3-phenyl-4-methoxyphenyl)aminopheny]ethyl}-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine,and5-[(R)-2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenylyethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one.Preferably, the β₂-adrenoreceptor agonist is a long actingβ₂-adrenoreceptor agonist (LABA), for example a compound which provideseffective bronchodilation for about 12 hours or longer.

Other β₂-adrenoreceptor agonists include those described in WO02/066422, WO 02/070490, WO 02/076933, WO 03/024439, WO 03/072539, WO03/091204, WO 04/016578, WO 2004/022547, WO 2004/037807, WO 2004/037773,WO 2004/037768, WO 2004/039762, WO 2004/039766, WO01/42193 andWO03/042160.

Preferred phosphodiesterase 4 (PDE4) inhibitors are cis4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylicacid,2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-oneandcis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cydohexan-1-ol].

Other suitable drug compounds include:cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid (also known as cilomalast) disclosed in U.S. Pat. No. 5,552,438 andits salts, esters, pro-drugs or physical forms; AWD-12-281 from elbion(Hofgen, N. et al. 15th EFMC Int Symp Med Chem (September 6-10,Edinburgh) 1998, Abst P.98; CAS reference No. 247584020-9); a9-benzyladenine derivative nominated NCS-613 (INSERM); D-4418 fromChiroscience and Schering-Plough; a benzodiazepine PDE4 inhibitoridentified as CI-1018 (PD-168787) and attributed to Pfizer; abenzodioxole derivative disclosed by Kyowa Hakko in WO99/16766; K-34from Kyowa Hakko; V-11294A from Napp (Landells, L. J. et al. Eur Resp J[Annu Cong Eur Resp Soc (September 19-23, Geneva) 1998] 1998, 12 (Suppl.28): Abst P2393); roflumilast (CAS reference No 162401-32-3) and apthalazinone (WO99/47505, the disclosure of which is hereby incorporatedby reference) from Byk-Gulden; Pumafentrine,(−)-p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[c][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamidewhich is a mixed PDE3/PDE4 inhibitor which has been prepared andpublished on by Byk-Gulden, now Altana; arofylline under development byAlmirall-Prodesfarma; VM554/UM565 from Vernalis; or T-440 (TanabeSeiyaku; Fuji, K. et al. J Pharmacol Exp Ther, 1998, 284(1): 162), andT2585.

Further compounds are disclosed in WO04/024728, WO04/056823 andWO04/103998, all of Glaxo Group Limited.

Suitable anticholinergic agents are those compounds that act asantagonists at the muscarinic receptor, in particular those compounds,which are antagonists of the M₁ or M₃ receptors, dual antagonists of theM₁/M₃ or M₂/M₃, receptors or pan-antagonists of the M₁/M₂/M₃ receptors.Exemplary compounds include the alkaloids of the belladonna plants asillustrated by the likes of atropine, scopolamine, homatropine,hyoscyamine; these compounds are normally administered as a salt, beingtertiary amines.

Other suitable anti-cholinergics are muscarinic antagonists, such as(3-endo)-3-(2,2-di-2-thienylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octaneiodide,(3-endo)-3-(2-cyano-2,2-diphenylethyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octanebromide,4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane bromide,(1R,5S)-3-(2-cyano-2,2-diphenylethyl)-8-methyl-8-{2-[(phenylmethyl)oxy]ethyl}-8-azoniabicyclo[3.2.1]octanebromide,(endo)-3-(2-methoxy-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octaneiodide,(endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octaneiodide,(endo)-3-(2-carbamoyl-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octaneiodide,(endo)-3-(2-cyano-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octaneiodide, and(endo)-3-{2,2-diphenyl-3-[(1-phenyl-methanoyl)-amino]-propyl}-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octanebromide.

Particularly suitable anticholinergics include ipratropium (e.g. as thebromide), sold under the name Atrovent, oxitropium (e.g. as the bromide)and tiotropium (e.g. as the bromide) (CAS-139404-48-1). Also of interestare: methantheline (CAS-53-46-3), propantheline bromide (CAS-50-34-9),anisotropine methyl bromide or Valpin 50 (CAS-80-50-2), clidiniumbromide (Quarzan, CAS-3485-62-9), copyrrolate (Robinul), isopropamideiodide (CAS-71-81-8), mepenzolate bromide (U.S. Pat. No. 2,918,408),tridihexethyl chloride (Pathilone, CAS-4310-35-4), and hexocycliummethylsulfate (Tral, CAS-115-63-9). See also cyclopentolatehydrochloride (CAS-5870-29-1), tropicamide (CAS-1508-75-4),trihexyphenidyl hydrochloride (CAS-144-11-6), pirenzepine(CAS-29868-97-1), telenzepine (CAS-80880-90-9), AF-DX 116, ormethoctramine, and the compounds disclosed in WO01/04118. Also ofinterest are revatropate (for example, as the hydrobromide, CAS262586-79-8) and LAS-34273 which is disclosed in WO01/04118, darifenacin(CAS 133099-04-4, or CAS 133099-07-7 for the hydrobromide sold under thename Enablex), oxybutynin (CAS 5633-20-5, sold under the name Ditropan),terodiline (CAS 15793-40-5), tolterodine (CAS 124937-51-5, or CAS124937-52-6 for the tartrate, sold under the name Detrol), otilonium(for example, as the bromide, CAS 26095-59-0, sold under the nameSpasmomen), trospium chloride (CAS 10405-02-4) and solifenacin (CAS242478-37-1, or CAS 242478-38-2 for the succinate also known as YM-905and sold under the name Vesicare).

Other anticholinergic agents include compounds disclosed in U.S. Ser.No. 60/487,981 and U.S. Ser. No. 60/511,009.

Suitable antihistamines (also referred to as H₁-receptor antagonists)include any one or more of the numerous antagonists known which inhibitH₁-receptors, and are safe for human use. All are reversible,competitive inhibitors of the interaction of histamine withH₁-receptors. Examples include ethanolamines, ethylenediamines, andalkylamines. In addition, other first generation antihistamines includethose which can be characterized as based on piperizine andphenothiazines. Second generation antagonists, which are non-sedating,have a similar structure-activity relationship in that they retain thecore ethylene group (the alkylamines) or mimic the tertiary amine groupwith piperizine or piperidine.

Examples of H1 antagonists include, without limitation, amelexanox,astemizole, azatadine, azelastine, acrivastine, brompheniramine,cetirizine, levocetirizine, efletirizine, chlorpheniramine, clemastine,cyclizine, carebastine, cyproheptadine, carbinoxamine,descarboethoxyloratadine, doxylamine, dimethindene, ebastine,epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen,loratadine, levocabastine, mizolastine, mequitazine, mianserin,noberastine, meclizine, norastemizole, olopatadine, picumast,pyrilamine, promethazine, terfenadine, tripelennamine, temelastine,trimeprazine and triprolidine, particularly cetirizine, levocetirizine,efletirizine and fexofenadine.

Exemplary H1 antagonists are as follows:

Ethanolamines: carbinoxamine maleate, clemastine fumarate,diphenylhydramine hydrochloride, and dimenhydrinate.

Ethylenediamines: pyrilamine amleate, tripelennamine HCl, andtripelennamine citrate.

Alkylamines: chlropheniramine and its salts such as the maleate salt,and acrivastine.

Piperazines: hydroxyzine HCl, hydroxyzine pamoate, cyclizine HCl,cyclizine lactate, meclizine HCl, and cetirizine

Piperidines: Astemizole, levocabastine HCl, loratadine or itsdescarboethoxy analogue, and terfenadine and fexofenadine hydrochlorideor another pharmaceutically acceptable salt.

Azelastine hydrochloride is yet another H₁ receptor antagonist which maybe used in combination with a PDE4 inhibitor.

The drug, or one of the drugs, may be an H3 antagonist (and/or inverseagonist). Examples of H3 antagonists include, for example, thosecompounds disclosed in WO2004/035556 and in WO2006/045416.

Other histamine receptor antagonists which may be used includeantagonists (and/or inverse agonists) of the H4 receptor, for example,the compounds disclosed in Jablonowski et al., J. Med. Chem.46:3957-3960 (2003).

Suitably, the drug formulation includes one or more of aβ₂-adrenoreceptor agonist, a corticosteroid, a PDE-4 inhibitor and ananti-cholinergic.

Generally, powdered drug particles suitable for delivery to thebronchial or alveolar region of the lung have an aerodynamic diameter ofless than 10 micrometers, preferably from 1-6 micrometers. Other sizedparticles may be used if delivery to other portions of the respiratorytract is desired, such as the nasal cavity, mouth or throat.

The amount of any particular drug or a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof which isrequired to achieve a therapeutic effect will, of course, vary with theparticular compound, the route of administration, the subject undertreatment, and the particular disorder or disease being treated. Thedrugs for treatment of respiratory disorders herein may for example, beadministered by inhalation at a dose of from 0.0005 mg to 10 mg,preferably 0.005 mg to 0.5 mg. The dose range for adult humans isgenerally from 0.0005 mg to 100 mg per day and preferably 0.01 mg to 1.5mg per day.

In one embodiment, the drug is formulated as any suitable aerosolformulation, optionally containing other pharmaceutically acceptableadditive components. In embodiments, the aerosol formulation comprises asuspension of a drug in a propellant. In embodiments; the propellant isa fluorocarbon or hydrogen-containing chlorofluorocarbon propellant.

Suitable propellants include, for example, C₁₋₄hydrogen-containingchlorofluorocarbons such as CH₂ClF, CClF₂CHClF, CF₃CHClF, CHF₂CClF₂,CHClFCHF₂, CF₃CH₂Cl and CClF₂CH₃; C₁₋₄hydrogen-containing fluorocarbonssuch as CHF₂CHF₂, CF₃CH₂F, CHF₂CH₃ and CF₃CHFCF₃; and perfluorocarbonssuch as CF₃CF₃ and CF₃CF₂CF₃.

Where mixtures of the fluorocarbons or hydrogen-containingchlorofluorocarbons are employed they may be mixtures of theabove-identified compounds or mixtures, preferably binary mixtures, withother fluorocarbons or hydrogen-containing chloro-fluorocarbons forexample CHClF₂, CH₂F₂ and CF₃CH₃. Preferably a single fluorocarbon orhydrogen-containing chlorofluorocarbon is employed as the propellant.Particularly preferred as propellants are C₁₋₄hydrogen-containingfluorocarbons such as 1,1,1,2-tetrafluoroethane (CF₃CH₂F) and1,1,1,2,3,3,3-heptafluoro-n-propane (CF₃CHFCF₃) or mixtures thereof.

The drug formulations are preferably substantially free ofchlorofluorocarbons such as CCl₃F, CCl₂F₂ and CF₃CCl₃. Preferably, thepropellant is liquefied HFA134a or HFA-227 or mixtures thereof.

The propellant may additionally contain a volatile adjuvant such as asaturated hydrocarbon for example propane, n-butane, liquefied, pentaneand isopentane or a dialkyl ether for example dimethyl ether. Ingeneral, up to 50% w/w of the propellant may comprise a volatilehydrocarbon, for example 1 to 30% w/w. However, formulations, which arefree or substantially free of volatile adjuvants are preferred. Incertain cases, it may be desirable to include appropriate amounts ofwater, which can be advantageous in modifying the dielectric propertiesof the propellant.

A polar co-solvent such as C₂₋₆ aliphatic alcohols and polyols e.g.ethanol, isopropanol and propylene glycol, preferably ethanol, may beincluded in the drug formulation in the desired amount to improve thedispersion of the formulation, either as the only excipient or inaddition to other excipients such as surfactants. In embodiments, thedrug formulation may contain 0.01 to 5% w/w based on the propellant of apolar co-solvent e.g. ethanol, preferably 0.1 to 5% w/w e.g. about 0.1to 1% w/w. In embodiments herein, the solvent is added in sufficientquantities to solubilise part or all of the drug component, suchformulations being commonly referred to as ‘solution’ aerosol drugformulations.

A surfactant may also be employed in the aerosol formulation. Examplesof conventional surfactants are disclosed in EP-A-372,777. The amount ofsurfactant employed is desirable in the range 0.0001% to 50% weight toweight ratio relative to the drug, in particular, 0.05 to 10% weight toweight ratio.

The aerosol drug formulation desirably contains 0.005-10% w/w,preferably 0.005 to 5% w/w, especially 0.01 to 2% w/w, of drug relativeto the total weight of the formulation.

In another embodiment, the drug is formulated as any suitable fluidformulation, particularly a solution (e.g. aqueous) formulation or asuspension formulation, optionally containing other pharmaceuticallyacceptable additive components.

Suitable formulations (e.g. solution or suspension) may be stabilised(e.g. using hydrochloric acid or sodium hydroxide) by appropriateselection of pH. Typically, the pH will be adjusted to between 4.5 and7.5, preferably between 5.0 and 7.0, especially around 6 to 6.5.

Suitable formulations (e.g. solution or suspension) may comprise one ormore excipients. By the term “excipient”, herein, is meant substantiallyinert materials that are nontoxic and do not interact with othercomponents of a composition in a deleterious manner including, but notlimited to, pharmaceutical grades of carbohydrates, organic andinorganic salts, polymers, amino acids, phospholipids, wetting agents,emulsifiers, surfactants, poloxamers, pluronics, and ion exchangeresins, and combinations thereof.

Suitable carbohydrates include monosaccharides include fructose;disaccharides, such as, but not limited to lactose, and combinations andderivatives thereof; polysaccharides, such as, but not limited to,cellulose and combinations and derivatives thereof; oligosaccharides,such as, but not limited to, dextrins, and combinations and derivativesthereof; polyols, such as but not limited to sorbitol, and combinationsand derivatives thereof.

Suitable organic and inorganic salts include sodium or calciumphosphates, magnesium stearate, and combinations and derivativesthereof.

Suitable polymers include natural biodegradable protein polymers,including, but not limited to, gelatin and combinations and derivativesthereof; natural biodegradable polysaccharide polymers, including, butnot limited to, chitin and starch, crosslinked starch and combinationsand derivatives thereof; semisynthetic biodegradable polymers,including, but not limited to, derivatives of chitosan; and syntheticbiodegradable polymers, including, but not limited to, polyethyleneglycols (PEG), polylactic acid (PLA), synthetic polymers including butnot limited to polyvinyl alcohol and combinations and derivativesthereof;

Suitable amino acids include non-polar amino acids, such as leucine andcombinations and derivatives thereof. Suitable phospholipids includelecithins and combinations and derivatives thereof.

Suitable wetting agents, surfactants and/or emulsifiers include gumacacia, cholesterol, fatty acids including combinations and derivativesthereof. Suitable poloxamers and/or Pluronics include poloxamer 188,Pluronic® F-108, and combinations and derivations thereof. Suitable ionexchange resins include amberlite IR120 and combinations and derivativesthereof;

Suitable solution formulations may comprise a solubilising agent such asa surfactant. Suitable surfactants includeα-[4-(1,1,3,3-tetramethylbutyl)phenyl]-ω-hydroxypoly(oxy-1,2-ethanediyl)polymers including those of the Triton series e.g. Triton X-100, TritonX-114 and Triton X-305 in which the X number is broadly indicative ofthe average number of ethoxy repeating units in the polymer (typicallyaround 7-70, particularly around 7-30 especially around 7-10) and4-(1,1,3,3-tetramethylbutyl)phenol polymers with formaldehyde andoxirane such as those having a relative molecular weight of 3500-5000especially 4000-4700, particularly Tyloxapol. The surfactant istypically employed in a concentration of around 0.5-10%, preferablyaround 2-5% w/w based on weight of formulation.

Suitable solution formulations may also comprise hydroxyl containingorganic co-solvating agents include glycols such as polyethylene glycols(e.g. PEG 200) and propylene glycol; sugars such as dextrose; andethanol. Dextrose and polyethylene glycol (e.g. PEG 200) are preferred,particularly dextrose. Propylene glycol is preferably used in an amountof no more than 20%, especially no more than 10% and is most preferablyavoided altogether. Ethanol is preferably avoided. The hydroxylcontaining organic co-solvating agents are typically employed at aconcentration of 0.1-20% e.g. 0.5-10%, e.g. around 1-5% w/w based onweight of formulation.

Suitable solution formulations may also comprise solublising agents suchas polysorbate, glycerine, benzyl alcohol, polyoxyethylene castor oilsderivatives, polyethylene glycol and polyoxyethylene alkyl ethers (e.g.Cremophors, Brij).

Suitable solution formulations may also comprise one or more of thefollowing components: viscosity enhancing agents; preservatives; andisotonicity adjusting agents.

Suitable viscosity enhancing agents include carboxymethylcellulose,veegum, tragacanth, bentonite, hydroxypropylmethylcellulose,hydroxypropylcellulose, hydroxyethylcellulose, poloxamers (e.g.poloxamer 407), polyethylene glycols, alginates xanthym gums,carageenans and carbopols.

Suitable preservatives include quatemary ammonium compounds (e.g.benzalkonium chloride, benzethonium chloride, cetrimide andcetylpyridinium chloride), mercurial agents (e.g. phenylmercuricnitrate, phenylmercuric acetate and thimerosal), alcoholic agents (e.g.chlorobutanol, phenylethyl alcohol and benzyl alcohol), antibacterialesters (e.g. esters of para-hydroxybenzoic acid), chelating agents suchas disodium edetate (EDTA) and other anti-microbial agents such aschlorhexidine, chlorocresol, sorbic acid and its salts and polymyxin.

Suitable isotonicity adjusting agents act such as to achieve isotonicitywith body fluids (e.g. fluids of the nasal cavity), resulting in reducedlevels of irritancy associated with many nasal formulations. Examples ofsuitable isotonicity adjusting agents are sodium chloride, dextrose andcalcium chloride.

Suitable suspension formulations comprise an aqueous suspension ofparticulate drug and optionally suspending agents, preservatives,wetting agents or isotonicity adjusting agents.

Suitable suspending agents include carboxymethylcellulose, veegum,tragacanth, bentonite, methylcellulose and polyethylene glycols.

Suitable wetting agents function to wet the particles of drug tofacilitate dispersion thereof in the aqueous phase of the composition.Examples of wetting agents that can be used are fatty alcohols, estersand ethers. Preferably, the wetting agent is a hydrophilic, non-ionicsurfactant, most preferably polyoxyethylene (20) sorbitan monooleate(supplied as the branded product Polysorbate 80).

Suitable preservatives and isotonicity adjusting agents are as describedabove in relation to solution formulations.

The drug dispenser device herein is in one embodiment suitable fordispensing aerosolized drug (e.g. for inhalation via the mouth) for thetreatment of respiratory disorders such as disorders of the lungs andbronchial tracts including asthma and chronic obstructive pulmonarydisorder (COPD). In another embodiment, the invention is suitable fordispensing aerosolized drug (e.g. for inhalation via the mouth) for thetreatment of a condition requiring treatment by the systemic circulationof drug, for example migraine, diabetes, pain relief e.g. inhaledmorphine.

Administration of drug in aerosolized form may be indicated for thetreatment of mild, moderate or severe acute or chronic symptoms or forprophylactic treatment. It will be appreciated that the precise doseadministered will depend on the age and condition of the patient, theparticular particulate drug used and the frequency of administration andwill ultimately be at the discretion of the attendant physician. Whencombinations of drugs are employed the dose of each component of thecombination will in general be that employed for each component whenused alone. Typically, administration may be one or more times, forexample from 1 to 8 times per day, giving for example 1, 2, 3 or 4aerosol puffs each time. Each valve actuation, for example, may deliver5 μg, 50 μg, 100 μg, 200 μg or 250 μg of a drug. Typically, each filledcanister for use in a metered dose inhaler contains 60, 100, 120 or 200metered doses or puffs of drug; the dosage of each drug is either knownor readily ascertainable by those skilled in the art.

In another embodiment, the drug dispenser device herein is suitable fordispensing fluid drug formulations for the treatment of inflammatoryand/or allergic conditions of the nasal passages such as rhinitis e.g.seasonal and perennial rhinitis as well as other local inflammatoryconditions such as asthma, COPD and dermatitis. A suitable dosing regimewould be for the patient to inhale slowly through the nose subsequent tothe nasal cavity being cleared. During inhalation the formulation wouldbe applied to one nostril while the other is manually compressed. Thisprocedure would then be repeated for the other nostril. Typically, oneor two inhalations per nostril would be administered by the aboveprocedure up to three 10 times each day, ideally once daily. Each dose,for example, may deliver 5 μg, 50 μg, 100 μg, 200 μg or 250 μg of activedrug. The precise dosage is either known or readily ascertainable bythose skilled in the art.

It will be understood that the present invention has been describedabove by way of example only and that the above description can bemodified in many different ways without departing from the scope of theinvention as defined by the appended claims.

All publications, patents, and patent applications cited herein, and anyUS patent family equivalent to any such patent or patent application,are hereby incorporated herein by reference to their entirety to thesame extent as if each publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

It must be noted that, as used in the specification and appended claims,the singular forms “a”, “an”, “the” and “one” include plural referentsunless the content clearly dictates otherwise.

The application of which this description and claims form part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described therein. They may take the form ofproduct, method or use claims and may include, by way of example andwithout limitation, one or more of the following claims.

1. A drug dispenser device comprising (a) a housing; (b) extending fromsaid housing, an outlet for insertion into a body cavity of a patient;(c) provided to the housing and moveable with respect thereto, a drugdischarge device, said drug discharge device having a longitudinal axisand comprising a container for storing a drug formulation to bedispensed, a discharge mechanism and a discharge channel from saidcontainer for discharge of said drug formulation to said outlet; (d)connecting to the drug discharge device, a container collar; (e)connecting to said container collar and moveable with respect theretoalong the longitudinal axis of the drug discharge device, a transferelement, said transfer element including an actuating portion; (f)provided to the housing, at least one finger operable member moveable toapply an actuating force to said actuating portion of said transferelement to move the transfer element from an initial transfer elementposition along the longitudinal axis in a first direction; (g) providedto the container collar, a pre-load mechanism to prevent transfer ofsaid actuating force to the container collar to move said drug dischargedevice along the longitudinal axis in the first direction to actuate thedischarge mechanism until a pre-determined threshold force is overcome;and (h) connecting the container collar with the transfer element, abiasing return mechanism acting to bias the transfer element along thelongitudinal axis in a second direction to return the transfer elementto the initial transfer element position.
 2. A drug dispenser deviceaccording to claim 1, wherein the housing is sized and shaped to enableone-handed operation of the dispenser device.
 3. A drug dispenser deviceaccording to either of claims 1 or 2, wherein the outlet is providedwith a removeable protective cover.
 4. A drug dispenser device accordingto any of claims 1 to 3, wherein the container has a cylindrical formand the longitudinal axis is defined by the central axis of thecylindrical container.
 5. A drug dispenser device according to any ofclaims 1 to 4, wherein the discharge channel extends out from the neckof the container.
 6. A drug dispenser device according to any of claims1 to 5, wherein the discharge channel is received by a cavity or passageprovided to a part of the housing, which cavity or passage enablescommunication with the outlet for dispensing of discharged drug to apatient.
 7. A drug dispenser device according to any of claims 1 to 6,wherein the container collar permanently engages with the container. 8.A drug dispenser device according to any of claims 1 to 7, wherein thecontainer collar engages with the neck of the container by means of asplit-ring collar provided thereto.
 9. A drug dispenser device accordingto any of claims 1 to 8, wherein the transfer element comprises anextension collar.
 10. A drug dispenser device according to claim 9,wherein the extension collar fits around the container collar.
 11. Adrug dispenser device according to any of claims 1 to 10, wherein theactuating portion defines an abutment surface.
 12. A drug dispenserdevice according to any of claims 1 to 11, wherein the at least onefinger operable member defines a bearing surface.
 13. A drug dispenserdevice according to any of claims 1 to 12, wherein the at least onefinger operable member is arranged to apply mechanical advantage.
 14. Adrug dispenser device according to claim 13, wherein said mechanicaladvantage has a ratio of from 1.5:1 to 10:1.
 15. A drug dispenser deviceaccording to claim 14, wherein the at least one finger operable membercomprises a lever.
 16. A drug dispenser device according to claim 15,wherein the at least one finger operable member comprises of at leastone lever pivotally connected to part of the housing.
 17. A drugdispenser device according to claim 16, wherein there are two opposinglevers, each of which pivotally connects to part of the housing andarranged to act upon the transfer element so as to urge the transferelement in the first direction when the two opposing levers are squeezedtogether by a user.
 18. A drug dispenser device according to either ofclaim 16 or 17, wherein the or each lever is pivotally supported at alower end of the housing.
 19. A drug dispenser device according to anyof claims 1 to 18, additionally comprising a locking mechanism forreversibly locking the movement of the at least one finger operablemember.
 20. A drug dispenser device according to any of claims 1 to 18,additionally comprising a locking mechanism for reversibly locking themovement of the container collar.
 21. A drug dispenser device accordingto claim 20, wherein said locking mechanism does not impede the movementof the at least one finger operable member and/or of the transferelement.
 22. A drug dispenser device according to any of claims 19 to21, wherein the locking mechanism comprises a locking element selectedfrom the group consisting of a limb, protrusion, and abutment.
 23. Adrug dispenser device according to any of claims 19 to 22, wherein thelocking mechanism is provided integral to a removeable cover for theoutlet.
 24. A drug dispenser device according to any of claims 1 to 23,wherein the biasing return mechanism comprises one or more springs. 25.A drug dispenser device according to claim 24, wherein the biasingreturn mechanism comprises an arrangement of two springs locating one oneither side of the container collar.
 26. A drug dispenser deviceaccording to either of claim 24 or 25, wherein the biasing returnmechanism comprises one or more extension springs.
 27. A drug dispenserdevice according to any of claims 1 to 26, wherein the pre-determinedthreshold force is in the range from 5 to 30N.
 28. A drug dispenserdevice according to any of claims 1 to 27, wherein the pre-loadmechanism is interposed between the container collar and the housing.29. A drug dispenser device according to claim 28, wherein the pre-loadmechanism comprises one or more detents provided to the container collarfor reversible engagement with part of the housing.
 30. A drug dispenserdevice according to claim 29, wherein the or each detent comprises aflexible support limb.
 31. A drug dispenser device according to claim30, wherein said flexible support limb is arranged for reversibleengagement with a step or abutment provided to the housing.
 32. A drugdispenser device according to either of claim 30 or 31, wherein thepre-load mechanism comprises an arrangement of from two to four flexiblesupport limbs.
 33. A drug dispenser device according to any of claims 30to 32, wherein a guide mechanism is provided to the extension collar forguiding the disengagement of the or each flexible support limb.
 34. Adrug dispenser device according to claim 33, wherein said guidemechanism comprises a guide ramp, which interacts with a shaped head ofthe or each flexible support limb.
 35. A drug dispenser device accordingto any of claims 30 to 34, wherein a reseat guide mechanism is providedto the extension collar for guiding the re-engagement of the or eachflexible support limb.
 36. A drug dispenser device according to claim35, wherein said reseat guide mechanism comprises a reseat guide ramp,which interacts with a shaped reseat head of the or each flexiblesupport limb.
 37. A drug dispenser device according to claim 28, whereinthe pre-load mechanism comprises one or more detents provided to thehousing for reversible engagement with part of the container collar. 38.A drug dispenser device according to any of claims 1 to 37, additionallycomprising an actuation counter.
 39. A drug dispenser device accordingto claim 38, wherein the actuation counter is actuable in response tomovement of the container collar or of the container along thelongitudinal axis in the first direction.
 40. A drug dispenser deviceaccording to claim 39, wherein the actuation counter is actuable inresponse to drive interaction with a driver element provided to thecontainer collar or container.
 41. A drug dispenser device according toclaim 40, wherein said driver element takes the form of a protrusion, anabutment, an indent or a slot provided to the container collar orcontainer.
 42. A drug dispenser device according to claim 39, whereinthe actuation counter is actuable in response to drive interaction witha driver element provided to a drive feature connecting to the containercollar or container.
 43. A drug dispenser device according to claim 42,wherein said driver element takes the form of a protrusion, an abutment,an indent or a slot provided to said drive feature.
 44. A drug dispenserdevice according to either of claim 42 or 43, wherein the drive featurecomprises a plate connecting to the container collar.
 45. A drugdispenser device comprising: a housing which comprises an outlet forinsertion into a body cavity of a patient, a drug discharge device inthe housing comprising a container for storing a drug formulation to bedispensed and a discharge mechanism for discharge of said drugformulation from said container to said outlet, the drug dischargedevice disposed in the housing such that the discharge mechanism is heldstationary and the container is movable in a first direction relative tothe discharge mechanism to put the device in a discharge mode where theformulation is discharged from the container to the outlet; a transferarrangement for transferring the container in the first directionrelative to the discharge mechanism comprising a first part attached tothe container, a second part connected to the first part so that thefirst and second parts are movable towards and away from each other, areturn biasing force mechanism for biasing the first and second parts toa resting configuration thereof, a latch adapted in use to latch thefirst part against movement in the first direction, and a latch releaseadapted for releasing the latch, when an actuating force of greater thana pre-determined threshold force is applied to the second part in thefirst direction, to enable the actuating force to move the first part inthe first direction and carry the container in the first directionrelative to the discharge mechanism to put the drug discharge device inits discharge mode.
 46. A drug dispenser device according to claim 45,additionally comprising an actuation counter configured and arranged tobe actuated by movement of the first part or the container in the firstdirection on release of the latch.
 47. A drug dispenser device accordingto either of claim 45 or 46, wherein the latch is provided on the firstpart and the latch release is provided on the second part.
 48. A drugdispenser device according to any of claims 45 to 47, wherein the firstpart is a collar.
 49. A drug dispenser device according to any of claims45 to 48, wherein the second part is a collar.
 50. A drug dispenserdevice according to any of claims 45 to 49, wherein the latch is formedby one or more projections of the first part.
 51. A drug dispenserdevice according to any of claims 45 to 50, wherein the latch release isformed by a surface thereof for contacting the latch for releasethereof.
 52. A drug dispenser device according to any of claims 45 to51, wherein the return biasing force is provided by a resilient element.53. A drug dispenser device according to claim 52, wherein the resilientelement is a spring.
 54. A drug dispenser device according to any ofclaims 45 to 53, wherein the device has an actuating mechanism formoving the second part of the transfer arrangement.
 55. A drug dispenserdevice according to claim 54, wherein the actuating mechanism comprisesat least one finger operable member.
 56. A drug dispenser deviceaccording to claim 55, wherein said at least one finger operable memberconsists of one or more levers.
 57. A drug dispenser device according toany of claim 38 to 44 or 46, wherein the actuation counter is providedas an assembly for insertion into the drug dispenser.
 58. A drugdispenser device according to any of claim 38 to 44 or 46 or 57, whereinan inner wall of the housing of the drug dispenser acts as a mountingfor some or all of the parts of the actuation counter.
 59. A drugdispenser device according to any of claim 38 to 44 or 46 or 57 or 58,wherein the actuation counter comprises one or more count wheelsprovided with count indicia thereon for display of the actuation count.60. A drug dispenser device according to claim 59, wherein the actuationcounter comprises: a first count wheel arranged to rotate about a firstaxis of rotation, said first count wheel including one or more drivereceipt elements arranged thereon for receipt of drive for drivablerotation of the first count wheel about said first axis of rotation; asecond count wheel arranged to rotate about the first axis of rotation,said second count wheel including a set of teeth arranged annularlythereon; and a kick wheel arranged to rotate about a second axis ofrotation offset from the first axis of rotation, said kick wheelincluding a set of kick teeth arranged annularly thereon and in meshedrelationship with the set of teeth of the second count wheel such thatrotary motion of the kick wheel results in rotary motion of the secondcount wheel, wherein said first count wheel further includes at leastone fixed index tooth arranged for intermittent meshing with the kickteeth of the kick wheel such that rotary motion of the kick wheelresults from rotary motion of the first count wheel only when saidintermittent meshing occurs.
 61. A drug dispenser device according toclaim 60, wherein the actuation counter is configured and arranged sothat said intermittent meshing is able to occur a plurality of times.62. A drug dispenser device according to either of claim 60 or 61,wherein the first or second count wheel has the form of a disc or aring.
 63. A drug dispenser device according to any of claims 60 to 62,wherein said one or more drive receipt elements of the first wheelcomprise one or more teeth and/or indents.
 64. A drug dispenser deviceaccording to any of claims 60 to 63, wherein the one or more drivereceipt elements of the first count wheel are arranged annularly.
 65. Adrug dispenser device according to claim 64, wherein the one or moredrive receipt elements of the first count wheel are arranged about aninner or outer circumferential wall of the first count wheel.
 66. A drugdispenser device according to any of claims 60 to 62 further comprisinga ratchet, and wherein the one or more drive receipt elements of thefirst count wheel comprise one or more ratchet drive receipt elementsarranged thereon for receipt of drive from said ratchet.
 67. A drugdispenser according to claim 66, wherein the ratchet is a ratchet wheelarranged for rotation about the first axis of rotation.
 68. A drugdispenser according to either of claim 66 or 67, wherein the ratchetwheel is provided with one or more ratchet drive tongues.
 69. A drugdispenser according to any of claims 66 to 68, wherein said one or moreratchet drive receipt elements are arranged annularly about the firstcount wheel.
 70. A drug dispenser according to any of claims 66 to 69,wherein the one or more ratchet drive receipt elements are selected fromthe group consisting of one or more teeth and indents.
 71. A drugdispenser according to any of claims 66 to 70, wherein at least one ofthe first and second count wheels has the form of a disc or a ring. 72.A drug dispenser according to claim 71, wherein the first count wheel isprovided with a circular cavity that is arranged for receipt of theratchet wheel, and the ratchet drive receipt elements are arranged aboutthe inner circumferential wall of the cavity for ratcheted driveinteraction with the ratchet wheel.
 73. A drug dispenser according toclaim 71, wherein the first count wheel has the form of a ring that isarranged for disposed receipt of the ratchet wheel, and the ratchetdrive receipt elements are arranged about the inner circumferential wallof the ring for ratcheted drive interaction with the ratchet wheel. 74.A drug dispenser according to any of claims 66 to 73, wherein theratchet is provided with one or more drive receipt elements for receiptof drive that results in movement thereof.
 75. A drug dispenseraccording to claim 74, wherein said one or more drive receipt elementsof the ratchet have a form selected from the group consisting of one ormore teeth, protrusions and indents.
 76. A drug dispenser according toany of claims 66 to 75, wherein the teeth of the second count wheel areprovided on an outwardly-facing circumferential surface of the secondcount wheel.
 77. A drug dispenser according to any of claims 66 to 75,wherein the second axis of rotation lies outside the path of rotationdefined by the second count wheel teeth.
 78. A drug dispenser accordingto any of claims 60 to 77, wherein the second count wheel teeth arearranged circumferentially on the second count wheel.
 79. A drugdispenser according to any of claims 60 to 78, wherein the second countwheel is arranged concentric to the first count wheel.
 80. A drugdispenser according to any of claims 60 to 79, wherein the second countwheel takes the form of a ring and the first count wheel is disposedwithin the ring.
 81. A drug dispenser according to any of claims 60 to80, wherein the kick teeth are arranged circumferentially on the kickwheel.
 82. A drug dispenser according to any of claims 60 to 81, whereinthe at least one index tooth is fixed at a point at or about thecircumference of the first count wheel and rotation of the first countwheel is arranged to bring the at least one index tooth into meshedrelationship with the kick teeth of the kick wheel at a particular pointof the rotary cycle of the first count wheel such that meshing occursonce during each complete rotation of the first count wheel.
 83. A drugdispenser according to any of claims 60 to 82, wherein the actuationcounter has a reverse rotation mechanism for interacting with either oneor both counter wheels to prevent reverse movement thereof.
 84. A drugdispenser according to claim 83, wherein the reverse rotation mechanismincludes a ratchet comprising a cam surface arranged to interact with acam follower provided to one or both of the count wheels.
 85. A drugdispenser according to claim 84, wherein the cam surface is shaped toassist correct alignment of the indicia on the count wheels to provide aclear count reading.
 86. A drug dispenser according to any of claims 60to 85, wherein the actuation counter includes a counter housing, whichhouses some or all of the other elements of the actuation counter.
 87. Adrug dispenser according to claim 86, wherein said counter housing isdefined at least in part by the housing of the drug dispenser.
 88. Adrug dispenser according to either of claim 86 or 87, wherein thecounter housing is shaped to define the first axis of rotation and thesecond axis of rotation.
 89. A drug dispenser according to claim 88,wherein the first count wheel mounts to the housing for rotation aboutthe first axis of rotation and the kick wheel mounts to the housing forrotation about the second axis of rotation.
 90. A drug dispenseraccording to any of claims 87 to 89, wherein the counter housing takesthe form of a bezel.
 91. A drug dispenser according to any of claims 87to 90, wherein the counter housing includes a viewing window throughwhich the count may be viewed.
 92. A drug dispenser according to claim91, wherein the actuation counter has a shutter to close off the viewingwindow at a predetermined point in the actuation counter operation. 93.A drug dispenser according to any of claims 60 to 92, wherein the firstand second count wheels are adapted in use to rotate in the same senseabout the first axis.
 94. A drug dispenser according to any of claims 60to 93, wherein the actuation counter has a display region through whichthe first and second count wheels are rotatable and a/the shutter whichis movable to a shuttering position in which it shutters the displayregion.
 95. A drug dispenser according to claim 94, wherein theactuation counter is so configured and arranged that the shutter is onlymovable to the shuttering position when the first and second countwheels are in predetermined angular positions about the first axis. 96.A drug dispenser according to either of claim 94 or 95, wherein theactuation counter is configured and arranged so that the shutter is onlyable to be moved to the shuttering position when the first count wheelhas rotated through a plurality of revolutions about the first axis. 97.A drug dispenser according to any of claims 94 to 96, wherein theactuation counter is configured and arranged such that the shutter movesto its shuttering position in response to movement of at least one ofthe count wheels.
 98. A drug dispenser according to any one of claims 94to 97, wherein the shutter is moved to its shuttering position by the atleast one count wheel.
 99. A drug dispenser according to claim 98,wherein the shutter is carried to the shuttering position by the atleast one count wheel.
 100. A drug dispenser according to any of claims97 to 99, wherein the at least one count wheel is the second countwheel.
 101. A drug dispenser according to any of claims 97 to 100,wherein the at least one count wheel and the shutter have cooperatingparts through which, in use, the at least one count wheel moves theshutter to its shuttering position.
 102. A drug dispenser according toany of claims 94 to 101, wherein the actuation counter is configured andarranged to display a count sequence with the count wheels and to causethe shutter to move to its shuttering position at the end of the countsequence.
 103. A drug dispenser according to any one of claims 92 and 94to 102, wherein the shutter is comprised in one of the count wheels.104. A drug dispenser according to claim 103, wherein the count wheel isintegrally formed with the shutter.
 105. A drug dispenser according toeither of claim 103 or 104, wherein the shutter overlies the other countwheel.
 106. A drug dispenser according to any of claims 103 to 105,wherein the shutter is comprised in the second count wheel.
 107. A drugdispenser according to any of claims 60 to 106, wherein the actuationcounter is configured and arranged to sequence from a count mode ofoperation, in which the first count wheel is able to drive rotation ofthe second count wheel through the kick wheel, to a non-count mode ofoperation, in which the first count wheel is unable to drive rotation ofthe second count wheel through the kick wheel.
 108. A drug dispenseraccording to claim 107, wherein the actuation counter is configured andarranged to sequence from the count mode to the non-count mode when thefirst count wheel has completed a predetermined number of revolutionsabout the first axis.
 109. A drug dispenser according to either of claim107 or 108, wherein the actuation counter is adapted to sequence fromthe count mode to the non-count mode when the second count wheel isdisposed in a predetermined angular orientation about the first axis.110. A drug dispenser according to any of claims 107 to 109, wherein theactuation counter is configured and arranged such that in the non-countmode meshing of the kick teeth with the index tooth and/or the secondcount wheel teeth is unable to occur.
 111. A drug dispenser according toclaim 110, wherein a gap is provided in the set of kick teeth or thesecond count wheel teeth to disable meshing in the non-count mode. 112.A drug dispenser according to any of claims 60 to 111, wherein theactuation counter is provided with a lock-out mechanism for locking theactuation counter at an end point of its operation.
 113. A drugdispenser according to claim 112, wherein the lock-out mechanism isadapted to cause the first count wheel to be locked against rotation.114. A drug dispenser device according to any of claims 1 to 113,wherein the drug discharge device is suitable for dischargingaerosolized drug and comprises an aerosol canister provided with adischarge valve having a valve stem.
 115. A drug dispenser deviceaccording to claim 114, wherein said valve stem is received within astem block provided to the housing, which stem block includes a passagethat acts such as to channel discharged aerosolized drug from the valvestem to the outlet.
 116. A drug dispenser device according to either ofclaim 114 or 115, wherein the outlet defines a mouthpiece.
 117. A drugdispenser device according to any of claims 114 to 116, wherein theaerosol canister comprises an aerosol drug formulation comprising a drugin a propellant.
 118. A drug dispenser device according to claim 117,wherein said propellant is a fluorocarbon or hydrogen-containingchlorofluorocarbon propellant.
 119. A drug dispenser device according toany of claims 1 to 113, wherein the drug discharge device is suitablefor discharging a spray of fluid drug and comprises a fluid containerprovided with a pump having a discharge tube.
 120. A drug dispenserdevice according to claim 119, wherein said discharge tube is receivedwithin a discharge tube block provided to the housing, which dischargetube block includes a passage that acts such as to channel dischargedfluid drug from the discharge tube to the outlet.
 121. A drug dispenserdevice according to either of claim 119 or 120, wherein the outletdefines a nozzle.
 122. A drug dispenser device according to any ofclaims 119 to 121, wherein the fluid container comprises a fluid drugformulation comprising a solution of drug in a solvent.
 123. A drugdispenser device according to any of claims 119 to 122, wherein thefluid container comprises a fluid drug formulation comprising asuspension of drug in a suspending agent.
 124. A drug dispenser deviceaccording to any of claims 1 to 123, additionally comprising a drugformulation in the container.
 125. A drug dispenser device according toclaim 124, wherein the drug of said drug formulation is ananti-inflammatory agent.
 126. A drug dispenser device according to claim125, wherein said anti-inflammatory agent is selected from the groupconsisting of a corticosteroid, an NSAID, a glucocorticoid compound andmixtures thereof.
 127. A drug dispenser device substantially asdescribed herein with reference to the accompanying drawings.
 128. Ahousing assembly for receipt of a drug discharge device, said drugdischarge device having a longitudinal axis and comprising a containerfor storing a drug formulation to be dispensed, a discharge mechanismand a discharge channel extending from said container for discharge ofsaid drug formulation, the housing assembly comprising (a) a housing;(b) extending from said housing, an outlet for insertion into a bodycavity of a patient; (c) a container collar for connection to the drugdischarge device; (d) connecting to said container collar and moveablewith respect thereto along the longitudinal axis of the drug dischargedevice, a transfer element, said transfer element including an actuatingportion; (e) provided to the housing, at least one finger operablemember moveable to apply an actuating force to said actuating portion ofsaid transfer element to move the transfer element from an initialtransfer element position along the longitudinal axis in a firstdirection; (f) provided to the container collar, a pre-load mechanism toprevent transfer of said actuating force to the container collar to movesaid drug discharge device along the longitudinal in the first directionto actuate the discharge mechanism until a pre-determined thresholdforce is overcome; and (g) connecting the container collar with thetransfer element, a biasing return mechanism acting to bias the transferelement along the longitudinal axis in a second direction to return thetransfer element to the initial transfer element position.
 129. Ahousing assembly for reversible receipt of a drug discharge devicesubstantially as described herein with reference to the accompanyingdrawings.